IMR Press / FBL / Volume 25 / Issue 1 / DOI: 10.2741/4795
Open Access Review
Metabolic approaches to rescue antitumor Vγ9Vδ2 T-cell functions in myeloma
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1 Laboratorio di Immunologia dei Tumori del Sangue (LITS), Centro Interdipartimentale di Ricerca in Biologia Molecolare (CIRBM), Università degli Studi di Torino, Turin, Italy;
2 Dipartimento di Oncologia, Università degli Studi di Torino, Turin, Italy;
3 SC Ematologia, AO S. Croce e Carle, Cuneo, Italy
Send correspondence to: Massimo Massaia, SC Ematologia, AO S. Croce e Carle, Via Michele Coppino 26, 12100 Cuneo, Italy; Tel.: 0171-642721, Fax: 0171-642209, E-mail:
Front. Biosci. (Landmark Ed) 2020, 25(1), 69–105;
Published: 1 January 2020
(This article belongs to the Special Issue Targeting of immune system in anti-tumor combined therapies)

Vγ9Vδ2 T cells are immune effector cells very well-suited for immunotherapy, but clinical results have been disappointing in multiple myeloma (MM) and other cancers. We have shown that Vγ9Vδ2 T cells are victimized prematurely by the immune suppressive tumor microenvironment (TME) established by myeloma and neighbouring cells in the bone marrow (BM) of MM patients. One major mechanism is the highly redundant expression of multiple immunecheckpoints/immune checkpoint-ligands (ICP/ICP-L) in the TME impairing antimyeloma Vγ9Vδ2 T-cell immune responses. Another major immune suppressive mechanism is the metabolic reset driven by myeloma cells in the TME to satisfy their energetic needs to the detriment of effector cells. Recently, it has become clear that the ICP/ICP-L circuitry and metabolic checkpoints (MCP) jointly operate in the TME of cancer patients to promote tumor cell growth and suppress antitumor immune responses. In this review, we discuss the possible interactions between ICP/ICP-L and MCP in the TME of MM patients that may compromise the immune competence of BM Vγ9Vδ2 T cells, envisaging novel combination therapies to improve the outcome of immune-based interventions.

Metabolic Checkpoints
Vγ9Vδ2 T cells
Immune Checkpoint
Multiple Myeloma
Tumor Microenvironment

Vγ9Vδ2 T cells are attractive candidates for ex-vivo and in vivo adoptive immunotherapy based on their capacity to bridge innate and adaptive immunity and to exert a multifaceted array of direct and indirect antitumor immune responses (1). Several in vitro data indicate that myeloma cells are privileged targets of Vγ9Vδ2 T cells, but clinical trials have fallen short of clinical expectations (2-4). We have shown that bone marrow (BM) Vγ9Vδ2 T cells are very susceptible to the immune suppressive context created by myeloma cells in the tumor microenvironment (TME) and very refractory to regain their immune competence status (5).

Vγ9Vδ2 T-cell dysfunction largely anticipates that of other immune effector cells, like CD8+ and CD4+ cells, indicating that, the initial myeloma cell expansion strategy, from the immunological standpoint, is aimed at neutralizing immune cells with the highest capacity to jeopardize myeloma cell growth and survival (5). The PD-1/PD-L1 axis is deeply involved in the neutralization of BM Vγ9Vδ2 T cells in MM (6,7), but single PD-1 blockade is insufficient to fully rescue in vitro the immune functions of Vγ9Vδ2 T cells (5). These data recapitulate the discouraging results of clinical trials in MM and other cancers (8, 9). Preliminary results from our laboratory indicate that the TME in MM patients is characterized by the expression of multiple immune checkpoints/immune checkpoint-ligands (ICP/ICP-L) in myeloma cells, immune effector cells, immune suppressor cells, bone marrow stromal cells (BMSC), and endothelial cells. This highly redundant ICP/ICP-L expression creates a very resilient immune suppressive network almost impossible to overcome by single ICP/ICP-L blockade.


The ICP/ICP-L circuitry is not the only molecular machinery involved in the establishment of the immune suppressive TME in MM and other cancers. Tumor cells must reprogram their metabolic pathways to support their expansion strategy against normal cells and immune cells in a microenvironment characterized by suboptimal vascularization and limited nutrients supply. To this end, tumor cells work for an increased rate of glycolysis and over-utilization of amino acids (i.e., glutamine, arginine, and tryptophan) resulting in the increased production of toxic waste in the TME. The combination of key nutrients deprivation and accumulation of immune suppressive metabolites (i.e., lactate, kynurenine, and adenosine) compromises the capacity of immune effector cells to mount effective antitumor immune responses as summarized in Figure 1 (10,11).

Figure 1

Metabolic alterations in the TME: consequences on tumor cells and immune cells. The energy supply needed by tumor cells to secure their survival and expansion in the TME is met by the enhanced utilization of nutrients locally available (i.e., glucose and amino acids). Far from being ecologically sustainable, the metabolic changes operated by tumor cells in the TME lead to the release of toxic waste that are responsible for the induction of a progressively hypoxic, acidic, and poor in nutrients TME. The immune cells respond in a different way to these challenges: toxic metabolites (i.e., lactate, kinurenines, Ado, etc) promote the activation of suppressor cells like Tregs, MDSC, M2 macrophages, whereas they restrain the activation of immune effector cells (Teffs). The metabolic reset operated by tumor cells (i.e., aerobic glycolysis, up-regulation of lipid/amino acid metabolism, etc) allows tumor cells to forestall the limited energetic resources locally available, whereas effector T cells are unable to reset their metabolism and fail the competition to secure the nutrients needed to support their activation. Immune suppressor cells also contribute to brake the immune reactivity of Teffs, that become functionally exhausted. The hypoxic and acidic features of the TME also contribute to the genetic and epigenetic instability of tumor cells promoting clonal evolution and immune escape. Many of the metabolic alterations summarized in this Figure have also been reported in the BM of MM patients.

The metabolic alterations occurring in the TME act as metabolic checkpoints (MCP) limiting not only the physiological immune surveillance exerted by innate and adaptive immunity, but also the efficacy of therapeutic immune interventions including ICP/ICP-L blockade. The rescue of immune effector cells by anti-PD-1 monoclonal antibodies (mAb) can be thwarted if the local TME is unfit to support the energetic needs of these cells once freed from the brake imposed by the PD-1/PD-1L network. So far, the most common strategy exploited to overcome inadequate ICP/ICP-L blockade has been the combination of multiple ICP/ICP-L inhibitors, but this approach is limited by the prohibitive costs and increased side effects. Our data in MM patients provide further evidence that the ICP/ICP-L circuitry is highly redundant and almost impossible to be resolved by single ICP/ICP-L blockade.

Mutations that activate oncogenic signaling pathways are progressively used as combination targets in onco-immunology to improve the efficacy of ICP/ICP-L blockade (12). An alternative approach is to target the interplay between ICP/ICP-L and MCP. Considerable efforts are underway to elucidate the mechanisms that MCP and ICP/ICP-L jointly operate in the TME to promote tumor cell growth and suppress antitumor immune responses (13).

This review will discuss how MCP can compromise the antitumor functions of immune effector cells, including Vγ9Vδ2 T cells, and whether targeting the affected pathways in combination with ICP/ICP-L blockade can be a powerful and cost-effective approach to enhance antitumor immune responses. We believe that the BM of MM patients is a very informative training-ground to address this issue and formulate novel hypotheses of therapeutic interventions based on concurrent MCP and ICP/ICP-L blockade.


The BM of MM patients is not exempted from the metabolic alterations occurring in the TME of other hematological and solid tumors (14,15). This metabolic reprogramming is finalized to meet the energetic needs of myeloma cells to the detriment of bystander cells with special regard to immune effector cells (14,16). Enhanced glycolysis (17) has been reported in myeloma cells to provide either fuel and/or building blocks for their survival and proliferation. Several mechanisms are involved in sustaining the enhanced glycolysis of myeloma cells. Hexokinase II (HKII), one of the pacemaker-enzyme of glycolysis, is constitutively over-expressed in myeloma cells, and HKII inhibition with 3-bromopyruvate (3BrPA) strongly suppresses ATP production leading to myeloma cell death (17). Pyruvate kinase M2 (PKM2) is another key player involved in the regulation of aerobic glycolysis to sustain tumor cell proliferation and survival. Alternative splicing of PKM isoforms by NIMA (never in mitosis gene A)-related kinase 2 (NEK2) promotes aerobic glycolysis in myeloma cells by increasing the PKM2/PKM1 ratio (18). Aerobic glycolysis is particularly accelerated in myeloma cells from patients with high-risk MM that are characterized by the aberrant expression of LDHA, PDK1 and GLUT1 (19).

Glutaminolysis is also increased in myeloma cells (14,20,21). Myeloma cells display high expression of glutamine transporters and are highly sensitive to glutamine depletion suggesting a glutamine-addicted status (20,22).

The toxic waste (e.g. lactate) generated by the increased utilization of glucose by myeloma cells and the accumulation of ATP breakdown products like adenosine (Ado) create a slightly acidic and hypoxic TME which, in combination with key nutrients depletion, promotes tumor cell survival and suppress antitumor immune responses (23-25).

Physiologically, the BM is already more hypoxic than the peripheral blood (26). This constitutive tendency to hypoxia is exacerbated in hematological malignancies arising in the BM like MM (27,28). Most changes induced by hypoxia are mediated by the transcription factor hypoxia-inducible factor-1 (HIF-1), consisting of HIF-1α and HIF-1β. The former is a cytosolic subunit degraded under normoxia, but which translocates into the nucleus under hypoxia; the latter is oxygen-insensitive protein constitutively present in the nucleus where it acts as HIF-1α co-activator. The dimer HIF-1α/HIF-1β, together with other isoforms such as HIF-2, is responsible for inducing several transcriptional programs in the hypoxic TME (27,28).

Interest in this area has been raised by the recognition that angiogenesis and disease progression are associated in MM and that hypoxia is a critical regulator of angiogenesis (29). Subsequent studies have confirmed that the BM of MM mouse models and MM patients is hypoxic compared to healthy controls (30,27) and that hypoxia plays a crucial role in triggering the metabolic alteration that are needed to sustain the growth of myeloma cells and promote their resistance to chemotherapy (27, 31-33).

Maiso and colleagues (34) have reported that the disease relapse in MM is initiated by residual myeloma cells which have become resistant to chemotherapy and are strategically located in the hypoxic niches of the TME. Drug resistance is gained via HIF-1α activation and up-regulation of the glycolytic enzymes HKII and lactate dehydrogenase A (LDHA). Development of melphalan resistance has also been associated with increased aerobic glycolysis and elevated oxidative stress response mediated by VEGF/IL8-signaling. In addition, up-regulated aldo-keto reductase levels of the AKR1C family involved in prostaglandin synthesis contribute to the resistant phenotype (35).

As expected, hypoxia has become a therapeutic target in MM and several approaches have been investigated in MM mouse models and human MM (28,30,36). Maiso et al have shown that the genetic knock-down of HIF-1α and/or LDHA restores the sensitivity of myeloma cells to bortezomib and melphalan (34). Glutaminolysis can also be involved in drug resistance since glutaminase 1, the pacemaker enzyme of glutaminolysis, is increased in bortezomib-resistant myeloma cell lines compared to sensitive cells (21). The anaplerotic flux driven by glutaminolysis fuels the tricarboxyclic acid (TCA) cycle and the mitochondrial oxidative phosphorylation (OXPHOS) to produce huge amounts of ATP. The selective glutaminase 1 inhibitor CB-839 reduces the availability of ATP and restores bortezomib sensitivity (37).

Very comprehensive reviews about the metabolic pathways that are significantly altered in myeloma cells vs normal B cells have recently been reported (38, 15). The hexosamine pathway, the amino acid interconversion reactions and degradation processes, the folate and the methionine cycle, the cholesterol uptake and metabolism, and the fatty acid synthase (FAS) are up-regulated especially in myeloma cells from MM patients with advanced disease.

Interestingly, the metabolic alterations occurring in the TME of MM patients are so robust to be mirrored in the peripheral blood. Steiner et al. have shown that the plasma levels of several metabolites derived from the amino acid, lipid, and classical catabolic pathways are significantly different in healthy volunteers compared to individuals with monoclonal gammopathy of undetermined significance (MGUS) and MM patients. IDO-driven immune regulation and glutaminolysis have emerged as the most promising therapeutic targets from this metabolomic analysis (16). Similar results have been reported by Du H et al. who have performed non-targeted metabolomic analyses on serum samples derived from responder and non- responder MM patients in comparison with healthy controls. The aim of the study was to identify non-invasive biomarkers for diagnosis and clinical monitoring of MM patients. They have identified 10 metabolites, mainly representative of the arginine/proline and glycerophospholipid metabolism, which were significantly different among groups and correlated with clinical outcome (39).

The metabolic changes occurring in the TME of MM patients are also responsible for the activation of pathway allowing myeloma cells to evade immune cell recognition and killing. Examples are the up-regulation of CD38, CD46, SLAMF7 (CS1), and ICP/ICP-L on myeloma cells and bystander cells (38). PKM2 has been reported to induce HIF-1α transactivation and recruitment of the hypoxia response elements (HRE) of HIF-1α target genes including PD-L1 on macrophages, dendritic cells (DCs), T cells, and tumor cells (40). Lactate and Ado-derivatives like cAMP generated by tumor cells in hypoxic TME can induce arginase (Arg-1) and indoleamine-2,3-dyoxigenase (IDO) activation in antigen presenting cells (APC). Arg-1 induced depletion of arginine, an essential amino acid to sustain T-cell proliferation, and arginine catabolism into urea and ornithine hampers the expansion of antitumor effector T cells. In parallel, kynurenine produced by IDO, that is up-regulated in the TME of MM patients, reinforces the inhibition of effector T cells and promotes the differentiation of regulatory T cells (Treg) (25). APC, myeloma cells and BMSC are the major IDO sources in the MM TME (41, 42) making this pathway an attractive metabolic target to increase the efficacy of antitumor immunotherapy (43).


The mevalonate (Mev) pathway has gained a great interest in the field when it was found that zoledronic acid (ZA), the most potent aminobisphophonate (NBP) commonly used to treat bone disease in MM and other solid cancers, can induce Vγ9Vδ2 T-cell activation. The mechanism consists in the inhibition of farnesyl-pyrophosphate synthase (FPPS) and accumulation of isopentenylpyrophosphate (IPP). IPP is structurally related to the phosphoantigens (pAgs) generated by mammalian and non-mammalian cells that Vγ9Vδ2 T cells recognize as part of their natural duty to react against pathogens, stressed cells, and tumor cells. Mev pathway up-regulation in myeloma cells is one reason why Vγ9Vδ2 T cells have a natural predisposition to recognize and kill myeloma cells in vitro (44, 45). As a result of the increased Mev pathway dysregulation, myeloma cells endogenously synthesize and release high amounts of IPP.

Mev is synthesised intracellularly from the 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) in a process catalysed by the rate-limiting enzyme HMG-CoA reductase (HMGR). The Mev pathway converts mevalonate into sterols (i.e, cholesterol) and nonsterol isoprenoids [i.e, FPP and geranylgeranylpyrophosphate (GGPP)]. Isoprenoids are critical for the isoprenylation of monomeric G-proteins such as Ras, Rho and Rac that are essential for cell growth and migration. FPP is specifically generated by FPPS, the enzyme targeted by ZA downstream to HMGR. The metabolic consequences of ZA-induced FPPS inhibition are both a reduced content of intracellular FFP-derived isoprenoids (leading to the impaired activity of prosurvival Ras-dependent pathways) (46), and intracellular IPP accumulation (47).

Intracellular IPP accumulation may have different fates depending on the cell capacity to handle the overload. In cells like osteoclasts and selected tumor cells, IPP is combined with AMP by aminoacyl-tRNA-synthetase and transformed into the pro-apoptotic ATP analog 1-adenosin-5-yl3-(3-methylbut-3-enyl) triphosphoric acid diester (ApppI) (48). ApppI accumulation induces apoptosis which is the mechanism exploited to treat bone disease in MM and cancer patients with bone metastases. On the contrary, cells like DC and BMSC are metabolically equipped to escape ApppI accumulation and apoptosis. We have shown that ATP-binding cassette transporter A1 (ABCA1) is involved with BTN3A1 and apoAI in the extrusion of intracellular IPP in DC, BMSC and other cells when IPP concentrations exceed a critical threshold (31,32). In these cells, the ABCA1/BTN3A1/apo-AI complex acts as safety valve to prevent ApppI formation and protect cell viability. The consequence of extracellular IPP can be different according to the releasing cells (i.e., DC vs BMSC) and the local microenvironment (i.e., TME vs secondary lymphoid organs) with the consequence to drive different functional outcomes in Vγ9Vδ2 T cells (i.e., activation vs functional exhaustion) (49,50).

The Mev pathway can also be targeted by statins that are potent HMGR inhibitors. By acting upstream to FPPS, statins suppress the entire pathway without inducing intracellular IPP accumulation. Both statins and ZA may have direct antitumor effects by inducing apoptosis and inhibition of myeloma cell proliferation (51-54). Interestingly, cytotoxicity of ZA against cancer cells is potentiated by hypoxia, via the loss of HMGR activity, suggesting that these drugs can outperform in cancer patients under hypoxic conditions (55).

Statins and ZA have also been shown to decrease P-glycoprotein-dependent multidrug resistance by reducing the Ras/ERK-dependent activation of HIF-1α (56,46). Mev pathway inhibition with simvastatin and lenalidomide has demonstrated a synergistic antimyeloma activity suggesting that this combination is worth investigating in the treatment of relapsed/ refractory MM (57). Unlike ZA, statins cannot activate Vγ9Vδ2 T cells because the Mev pathway inhibition is up-stream to FPPS and there is no IPP accumulation. Thus, ZA only can be used to intentionally activate antitumor immunity mediated by Vγ9Vδ2 T cells (58, 47) and NK cells (59,60). However, Vγ9Vδ2 T-cell based immune interventions in MM have not met clinical expectations. Our interpretation is that the protumoral partnership operated by ICP/ICL and MCP has been underestimated and the strategies fielded to rescue Vγ9Vδ2 T-cell functions inadequate.


Very few data are available about the impact of TME metabolic alterations on Vγ9Vδ2 T cells. Figure 2 illustrates the expected interplay between metabolic alterations occurring in myeloma cells and immune cells in the TME of MM patients. It is very unlikely that Vγ9Vδ2 T cells can escape the metabolic constraints elaborated by myeloma cells and bystander cells in the TME of MM patients. As reported above, Vγ9Vδ2 T cells are more susceptible to immune suppression than other immune effector cells as shown by PD-1 expression and anergy to pAg stimulation already detectable in MGUS individuals, when the BM myeloma cell infiltration is minimal (< 10% by definition) and the disease totally asymptomatic.

Figure 2

Metabolic pathways involved in the immune suppressive TME of MM patients. Anaerobic and aerobic glycolysis, fatty acid β-oxidation, glutaminolysis, and oxidative phosphorylation are metabolic pathways supplying energy and building blocks to myeloma cells (MM cells) The mevalonate pathway (Mev) provides building blocks (cholesterol, isoprenoids) and phosphoantigens (i.e. IPP) that can activate or inhibit Vγ9Vδ2 T cells depending on local concentrations. ATP-degradation via CD39 and CD73, arginine and tryptophan catabolism via Arginase-1 (Arg-1) and indoleamine 2,3-dioxygenase (IDO) are catabolic pathways operative in myeloma cells and neighboring cells (myeloid-derived suppressor cells, MDSC; bone marrow stromal cells, BMSC) that contribute to the generation of the immunosuppressive tumor microenvironment (TME). Hypoxia and the transcription factor hypoxia inducible factor-1α (HIF-1α) promote anaerobic glycolysis and up-regulate the immune-checkpoint (ICP) PD-L1 and the ATP binding cassette transporter ABCA1. ABCA1 in cooperation with apolipoprotein A-I (apoA-I) and butyrophilin-3A1 (BTN3A1) extrudes supra-physiological IPP amounts from myeloma cells and BMCS leading to Vγ9Vδ2 T-cell exhaustion.

Like conventional T cells, Vγ9Vδ2 T cells need to reset their metabolism when they are engaged by specific challenges and must mount an effective immune response. Vγ9Vδ2 T cells can also be divided into subsets according to their phenotype, proliferative capacity and effector functions. Naïve and memory Vγ9Vδ2 T cells (both CD27+) display high proliferative capacity, but low effector functions, whereas effector and late effector Vγ9Vδ2 T cells (both CD27-) display the opposite pattern (61). Naïve T cells oxidize glucose-derived pyruvate, along with lipids and amino acids, to efficiently produce ATP/energy required for immune surveillance. Upon activation, fatty acid oxidation (FAO) is down-regulated, and glycolysis and glutaminolysis up-regulated to quickly produce enough energy to sustain the rapid cell growth and proliferation requirements. At the end of the immune response, cells committed to become memory T cells revert to FAO which is more efficient to generate energy under less stressful conditions (62).

This metabolic reset is challenged in the TME which is intrinsically hostile to the immune system and metabolically committed to promote tumor cell survival, restrain antitumor immune responses, and concurrently boost protumoral immune responses as illustrated in Figure 1 and Figure 2.

No data are available about the metabolic reset operated by Vγ9Vδ2 T cells challenged by tumor cells in the TME, but some interesting speculations can be inferred from experimental models and the behavior of other innate effector cells. Laird et al have investigated glucose metabolism in a Listeria mouse model of infection and shown that γδ T cells express higher surface levels of glucose transporters than αβ T cells. γδ T cells exhibit effector functions over a broader range of glucose concentrations after activation, suggesting a greater dependency on glucose uptake and metabolism than activated αβ cells (63). This metabolic behavior is reminiscent of what NK cells operate to boost aerobic glycolysis and sustain IL-15-driven differentiation and activation (64). The greater γδ T-cell dependency on glycolysis may explain why the dysfunction of Vγ9Vδ2 T cells is already detectable in MGUS and anticipates the immune dysfunctions of CD4+ and CD8+ cells.

Another major MCP constraint limiting the antitumor activity of CD8+ T cells and NK cells (65, 66) is amino acid depletion which reinforces the immune suppressive effects of glucose deprivation in the TME (67-69). Glutamine deprivation suppresses T-cell proliferation and cytokine production by preventing Th1-cell differentiation, while fostering Treg development (70). We are currently investigating whether the glutamine deprivation reported in the TME of MM patients (22) can contribute to Vγ9Vδ2 T-cell dysfunction and whether strategies preventing glutamine deprivation can help to rescue their immune competence.

Alterations in arginine metabolism also have a critical role in modulating antitumor immune responses. L-Arginine is necessary to promote T-cell cycle progression and switch from glycolysis to oxidative phosphorylation (OXPHOS), and to sustain the generation of memory T cells (71). L-Arginine is a critical energy resource for effector T cells in a glucose-deprived TME, but the TME operates to minimize its concentrations and blunt T-cell activation. Tumor cells produce metabolites (i.e, cAMP, lactate or HIF-1α-induced molecules) and cytokines (i.e, IL-4, IL-6, IL-13, M-CSF or GM-CSF) that up-regulate arginase 1 (Arg1) expression in tumor-associated macrophages and MDSC leading to L-arginine degradation and suppression of T-cell effector functions (72). This immune suppressive mechanism is operated by myeloma cells and MDSC in the TME of MM patients (73). Sacchi A. et al. have argued that Arg1 up-regulation and L-arginine deprivation can be involved in the immunosuppression of Vγ9Vδ2 T cells mediated by MDSC (74). Accordingly, Arg1 inhibition restores the ability of Vγ9Vδ2 T cells to produce IFN-γ production and kill Daudi and Jurkat cells overcoming MDSC-induced immunosuppression (74).

Another major MCP is the increased tryptophan catabolism mediated by IDO and leading to increased kynurenine levels in the TME. On the one hand, tryptophan deprivation impairs T-cell proliferation and cytotoxic T-cell responses (75); on the other, the overproduction of kynurenines in the TME induces Treg differentiation and suppresses T-cell effector functions by downregulating the T-cell receptor CD3 ζ chain (76,77). Like other MCP, tryptophan catabolism P operates in the TME to tip the balance in favor of Treg to the detriment of effector T cells. Based on these data, it is not surprising that Treg are steadily rooted in the BM of MM patients irrespectively of the disease status and never loose their capacity to blunt antimyeloma immune responses, including those mediated by Vγ9Vδ2 T cells (78). Interestingly, Kunzmann et al. have reported that Treg can specifically suppress Vγ9Vδ2 T cells in MM patients (79). The uncontrolled production of kynurenine by IDO, largely overexpressed in the MM TME (41,42), can also contribute to Vγ9Vδ2 T-cell immune suppression. Data by Fechter K et al support this hypothesis since they have shown kynurenines produced by BM mesenchimal stem cells can affect Vγ9Vδ2 T-cell activation (80).

Hypoxia is another major hurdle to antimyeloma immune responses mediated by Vγ9Vδ2 T cells. HIF-1α can promote the generation and maintenance of Treg cells (81) and induce the expression of PD-L1 in tumor cells and MDSC (82-85). We have reported that MDSC are PD-L1+ in the TME of MM patients and these cells do not fade away even when almost all myeloma cells have been eliminated by autologous stem cell transplantation (5). Very few data are available about the effect of hypoxia on Vγ9Vδ2 T-cell functions. Siegers GM and colleagues (86) have found an increased infiltration of Vγ9Vδ2 T cells in the hypoxic areas of breast cancer patients, but MIC-A shedding protects breast cancer cells from Vγ9Vδ2 T-cell recognition and killing. More recently, it has been shown in vivo that MDSC can modulate the cytotoxicity of γδ T cells via tumor-derived exosomes engaged by the miR-21/PTEN/PD-L1 axis (87). We have initiated to evaluate the effect of hypoxia on pAg-reactivity of normal Vγ9Vδ2 T cells and found that it is almost completely abrogated. We are currently investigating whether this is a direct consequent of HIF-1α activity or a consequence of HIF-1α-driven metabolic reprogramming.

Another major MCP which can restrain Vγ9Vδ2 T-cell functions is Ado, whose concentrations are elevated in the TME of MM patients due to the coordinated expression of adenosinergic ecto-nucleotidases (CD39/CD73/CD38/CD203a) strategically located in the hypoxic BM niches (88, 89). The immune suppressive effect of Ado on conventional effector T cells is well known (90), whereas no data are available onVγ9Vδ2 T cells. Data in a mouse model of experimental autoimmune uveitis indicate that γδ T cells (not Vγ9Vδ2 T cells because mice lack this subset) have an increased expression of high-affinity adenosine receptors (A2ARs) and that A2AR ligation inhibits αβ T cell activation, but enhances γδ T cell activation (91). The high A2ARs expression enables γδ T cells to sequester Ado, prevents Treg expansion, and unleashes αβ T-cell activation (92). Whether similar interactions between Ado, Treg, conventional αβ T cells and Vγ9Vδ2 T cells also occur in humans is unknown. We have previously reported that ZA induces an advantageous cross-talk in MM between Vγ9Vδ2 T cells, αβ CD8+ T cells, regulatory T cells, and DC, but these data were obtained using PB cells and not cells isolated from the TME (47).

An additional layer of metabolic complexity that Vγ9Vδ2 T cells have to cope with in the TME is due to their unique ability to recognize pAgs generated in the Mev pathway of tumor cells and bystander cells. We have shown that BMSC in the TME of MGUS and MM patients release huge amounts of IPP which can be regarded as a MCP highly specific for Vγ9Vδ2 T cells. We have shown that IPP release in the TME by BMSC is an early event already detectable in MGUS individuals. This long-lasting exposure to IPP can be responsible for the early senescence experienced by Vγ9Vδ2 T cells in the TME of MGUS and MM (6). These data are in keeping with the serum metabolomic profiles of MGUS (see above) which already different compared with healthy controls indicating that some metabolic alterations occur very early in the biology of MGUS/MM evolution similar to the dysfunction affecting Vγ9Vδ2 T cells.


Immunotherapy in cancer has finally burst on the clinical scene after being questioned for many years. Most of the breakthrough has been triggered by monoclonal antibodies (mAbs) blocking ICP/ICP-L interactions, but several issues remain to be solved to fully exploit this long-sought therapeutic opportunity. It is not known which are the most effective immune cells to be rescued from immune suppression and to be redirected against tumor cells (i.e., CD8+ cells, NK cells, NKT cells, Vγ9Vδ2 T cells, etc). Likewise, it is not known which is the best combination therapy since single PD-1/PD-L1 blockade is inadequate in many cancers, including MM. The metabolic alterations occurring in the TME of MM patients are therapeutic targets very promising because of the interplay with ICP/ICP-L and their potential druggability using small (and often inexpensive) molecules which are very well suited to target intracellular pathways (93-95).

Targeting MCP in combination with ICP/ICP-L blockade can enhance antimyeloma Vγ9Vδ2 T-cell functions and improve the efficacy of immune-based interventions in MM and other cancers. Speculative combination strategies are discussed below and graphically summarized in Figure 3.

Figure 3

Possible strategies to rescue Vγ9Vδ2 T cells by targeting MCP in combination with ICP/ICP-L blockade in MM. MCP are shown in the grey ellipse; the relative activatory/inhibitory molecules are shown in the colored circles. A. Glycolytic and intermediate metabolism (light blue): myeloma cells exhibit high expression of glucose transporter 4 (GLUT4) for basal glucose consumption, whose uptake can be override by HIV protease inhibitor ritonavir. The combination of ritonavir and metformin can improve antimyeloma activity, while dichloroacetate, an inhibitor of anaerobic glycolysis, can increase the sensitivity of myeloma cells to chemotherapeutic drugs. Pyruvate kinase isoform M2 (PKM2) is also a co-stimulator of hypoxia-inducible factor 1α (HIF-1α) activity and inducer of cPD-L1 inducer in several immune cells. TEPP-46, a PKM2 inhibitor, can down-regulate PD-L1 expression in myeloma cells and neighbouring cells favouring the rescue of Vγ9Vδ2 T cells; B. TCA cycle and mitochondrial metabolism (light green): The TCA inhibitors phosphonoethyl ester of succinyl phosphonate (an α-ketoglutarate dehydrogenase - α-KGDH - inhibitor) and AGI-6780 (an isocitrate dehydrogenase – IDH - inhibitor), the glutaminolysis inhibitor BPTES, and the electron transport chain (ETC) inhibitor α-tocopheryl succinate (α-TOS) are FDA-approved agents under clinical evaluation in several tumors and potentially applicable also to MM. Drugs that induce mitochondria destabilization have emerged as good target for anti-cancer drugs. In particular, retrieving the activity of PGC1α, a transcription factor that promotes mitochondrial biogenesis, may allow to improve the defective mitochondrial mass of immune effector cells in TME, including Vγ9Vδ2 T cells, promoting their activation and cytotoxic functions. C. Hypoxia (grey): The hypoxic TME in MM BM niche leads to the up-regulation of HIF-1α, a strong transcriptional inducer of GLUT and glycolytic enzymes. The inhibition of HIF-1α synthesis or nuclear translocation may be an effective way to reduce glycolytic fluxes in myeloma cells to make glucose available to immune effector cells, including Vγ9Vδ2 T cells. The electron transport chain (ETC) in myeloma cells contribute to hypoxia in the TME and ETC inhibitors can improve the efficacy of ICP/ICP-L blockade by reducing hypoxia in the BM of MM patients. D. Mev pathway (orange): Inhibition of acetyl citrate lyase (ACLY) and acetyl-CoA acetyltransferase-1 (ACAT1) enhances the pro-immunogenic effects of chemotherapy and the efficacy of the antitumor T cells in preclinical models. The Mev pathway can be targeted by HMGCR inhibitors, like statins, or by nitrogen containing bisphophonates (N-BP), like zoledronic acid (ZA). By inhibiting farnesyl pyrophosphate synthase (FPPS), ZA induces the intracellular accumulation of isopentenyl pyrophosphate (IPP) which is recognized by Vγ9Vδ2 T cells. Both statins and N-BP have also direct antitumor effects, inducing apoptosis and inhibiting proliferation of MM. E. Fatty acid metabolism (dark blue): The fatty acid synthase (FAS) and the fatty acid oxidation (FAO) may support respectively the proliferation and differentiation of effector and memory cells, including Vγ9Vδ2 T cells. Long-lasting memory-like T cells rely preferentially on mitochondrial OXPHOS for their energetic demands. Fenofibrate, a PPAR-α activator that increases FAO, sustains the immune competence of CD8+ TIL preventing their functional exhaustion and synergizes with anti-PD-1 blockade. Similarly, chemical agents enhancing OXPHOS in CD8+ TIL enhanced the efficacy of anti-PD1 treatments in solid tumors. Etomoxir has been used to deprive myeloma cells of FA via inhibition of carnitine palimtoyl transferase 1 (CPT1), the pace-maker enzyme in FAO, yielding to a significant suppression of myeloma cell proliferation. The combination of etomoxir with orlistat (a FAS inhibitor) synergistically suppresses myeloma cell growth and enhances sensitivity to bortezomib. F. Amino acid metabolism (pink): IDO inhibitors can rescue dysfunctional or exhausted T cells by restoring tryptophan levels in the TME. Arginine metabolism can be modulated in the TME both by Arg1 inhibition and by targeting its conversion into citrulline by ADI-PEG20. Also PDE5 inhibitors down-regulate Arg1 and nitric oxide synthase–2 (NOS2) expression. Glutamine metabolism can be targeted by glutamine analogs, inhibitors of glutamine transporters or inhibitors of glutamate conversion to α-ketoglutarate. G. Ado pathway (dark green): the ecto-enzymes CD73, CD39, and CD38, and Ado receptors (A2AR) are druggable MCP. A2AR inhibitors, anti-CD73 mAb, anti-CD39 mAb and anti-CD38 mAb therapy demonstrated antitumor activity both in monotherapy as well as in combination with PD-1/PD-L1 blockade.

7.1. Combination with drugs targeting glycolytic and intermediate metabolism

Glucose consumption is one MCP granting cancer cell survival, restricting T-cell activation and promoting resistance to adoptive T-cell therapy (96). Both anaerobic and aerobic glycolysis are amenable to therapeutic intervention. Myeloma cells exhibit increased activity in glucose transporters of GLUT family like GLUT1, GLUT4, GLUT8 and GLUT11, and in glycolytic enzymes like HK (97). Interestingly, myeloma cells rely on the insulin-responsive glucose transporter GLUT4 for basal glucose consumption, maintenance of Mcl-1 expression, growth, and survival. The FDA-approved HIV protease inhibitor ritonavir acts as a GLUT4 off-target inhibitor abrogating both glucose uptake and proliferation on KMS11 and L363 myeloma cells (97). Interestingly, some myeloma cells can survive to glucose deprivation and/or ritonavir treatment because they switch to OXPHOS to support their energetic needs. Metformin is an FDA approved antidiabetic medication that targets mitochondrial complex 1. The combination of ritonavir and metformin in vitro induces the apoptosis of myeloma cell lines and human primary myeloma cells, and the same combination has shown antimyeloma activity in vivo in a xenograft myeloma mouse model (98). Inhibition of AKT and mTORC1 phosphorylation in combination with Mcl-1 down-regulation have been advocated as key mechanisms (98), but it is also possible that a major contribution comes from the energetic crash induced by the ritonavir and metformin combination. Dichloroacetate, an inhibitor of anaerobic glycolysis, has been reported to increase myeloma cell sensitivity to bortezomib (99), and Zub et al. have confirmed that inhibition of aerobic glycolysis increases sensitivity of myeloma cells to melphalan (100).

Pyruvate kinase isoform M2 (PKM2) catalyzes the final rate-limiting glycolytic reaction and plays a key role in cancer cell metabolism and immune responses. Furthermore, PKM2 dimers can translocate into the nucleus and stimulate HIF-1α-dependent transcriptional activity. Intriguingly, PD-L1 is up-regulated by PKM2 and HIF-1α in macrophages, DC, T cells and tumor cells. The small molecule TEPP-46 partially relieves the immune suppressive TME contexture by down-regulating PD-L1 expression via PKM2 inhibition (101). Additional ICP/ICP-L blockade (i.e., TIM3, LAG-3 etc) can further improve TEPP-46 activity and ameliorate antitumor immune responses.

ICP/ICP-L blockade itself can down-regulate glycolytic fluxes. Anti- ICP/ICP-L mAbs in combination with glycolytic inhibitors can restrain the extensive glucose uptake and utilization by tumor cells and redirect this energy resource towards effector T cells to sustain their reactivity and expansion (94). The increased glycolytic flux in tumors is controlled by AKT/mTOR pathway that up-regulates the glucose uptake via specific GLUT transporters and glycolytic enzymes (67). Anti-PD-L1 mAbs reduce glycolysis in cancer cells by inhibiting Akt/mTOR signaling making glucose also available to T cells to fuel their metabolic needs and mount antitumor immune responses (67, 102, 94). A plus for ICP/ICP-L mAbs compared with traditional glycolytic inhibitors (i.e, fasentin, lonidamine, phosphonoacetohydroxamate, galloflavin, etc) is that they target more specifically tumor cells. The combination of ICP/ICP-L inhibitors with sub-therapeutic concentrations of glycolytic inhibitors (to prevent side effects) can have synergistic effect on the antitumor activity of T cells in the TME.

Akt/mTOR inhibitors also can be combined with ICP/ICP-L mAbs to promote a fairer glucose redistribution in the TME. Interestingly, it has been reported a tight association between ICP-L expression and mTOR activity in cancer cells (103) suggesting that their concurrent inhibition can result in two therapeutic effects: 1) inhibition of tumor cell growth by interfering with the pro-survival pathways driven by Akt/mTOR signaling; 2) suppression of glucose over-utilization by tumor cells and recovery of antitumor immune functions, including Vγ9Vδ2 T cells. Lastly, the combination of ICP/ICP-L blockade and Akt/mTOR inhibition could also increase the sensitivity of myeloma cells to conventional chemotherapy opening the way to triple combination treatments.

7.2. Targeting the TCA cycle and mitochondrial metabolism

The TCA cycle and OXPHOS are mitochondrial pathways acting downstream to aerobic glycolysis. The TCA cycle benefits also from the anaplerotic fluxes of FAO and glutaminolysis. These pathways are able to provide long-term energy supply and provide building blocks for proliferating cells and immune cells undergoing functional differentiation.

Myeloma cells rely on the TCA cycle, including its anaplerotic fluxes, and OXPHOS to meet their energy requirements (14, 15, 104). Disruption of these energy sources has a strong impact on tumor cell survival and proliferation. Mitochondria have emerged as an intriguing target for anticancer drugs, inherent to the great majority of tumors. Drugs that target mitochondria and exert anticancer activity have been termed 'mitocans' to outline their ability to induce mitochondria destabilization (105). The TCA inhibitors phosphonoethyl ester of succinyl phosphonate (an α-ketoglutarate dehydrogenase inhibitor) and AGI-6780 (an isocitrate dehydrogenase – IDH - inhibitor), the glutaminolysis inhibitor BPTES, and the electron transport chain (ETC) inhibitor α-tocopheryl succinate (complex II inhibitor) are FDA-approved agents under clinical evaluation in several tumors and potentially transferable to MM. Targeting the mitochondrial metabolism has also already been explored in MM patients in combination with proteasome inhibitors. The combination of carfilzomib and the IDH2 inhibitor AGI-6780 is lethal to primary myeloma cells in vitro because the TCA cycle is disrupted and ATP is no more available. Since IDH2 is activated by the NAD+-dependent deacetylation mediated by sirtuin-3, the use of NAD+-generating enzyme nicotinamide phosphoribosyltransferase (NAMPT) inhibitors is another potential tool to improve the efficacy of carfilzomib and overcome the development of carfilzomib resistance (106).

Mitocans are not exempted from detrimental effects because mitochondrial biogenesis is also required by effector T cells to mount effective antitumor immune responses. Tumor-infiltrating lymphocytes (TIL) are characterized by low mitochondrial mass and metabolic flux due to the Akt-mediated inhibition of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α), a transcription factor that promotes mitochondrial biogenesis. Restoring the activity of PGC1α corrects the defective mitochondrial mass and increases the energy supply for TIL, promoting their sustained activation and effector functions (107). Mitochondrial biogenesis is emerging as critical issue also to improve the efficacy and duration of chimeric antigen receptor (CAR) redirected T cells (CAR-T cells). The costimulatory domain 4-1BB has replaced CD28 in the architecture of second-generation CAR-T cells because it promotes the outgrowth of CD8+ memory T cells, which have significantly better respiratory capacity, increased FAO and enhanced mitochondrial biogenesis (108). Very recently, Van Bruggen et al. have reported that the clinical efficacy of CAR-T cells in CLL is dependent on their mitochondrial mass which can be regarded as an indirect evidence of their capacity to successfully compete with energy sources in the TME (109).

Unfortunately, mitocans, like other metabolic correctors, are penalized by the lack of specificity leading to contrasting effects on tumor cells and immune effector cells in the TME. It is a matter of debate whether the conjugation of mitocans with tumor-selective ligands and/or the conjugation of mitochondrial reactivating agents (e.g. PGC1α inducers) with T-lymphocytes-targeting ligands may overcome this impasse. Conjugation of mitochondrial activators with pAgs specifically recognized by Vγ9Vδ2 T cells may represent a promising strategy to improve the selectivity of metabolic correctors.

7.3. Combination with hypoxia inhibitors

The hypoxic TME in MM BM leads to the constitutive up-regulation of HIF-1α, a strong transcriptional inducer of GLUT and glycolytic enzymes. Therefore, HIF-1α inhibition can decrease glucose utilization by myeloma cells making glucose available to immune effector cells including Vγ9Vδ2 T cells. Unfortunately, HIF-1 inhibitors have failed clinical expectations so far, probably because they lack specificity (110). Oxygen consumption by ETC in tumor cells is also under investigation as a targetable MCP. Hypoxia promotes ICP/ICP-L expression via HIF-1α activation and other mechanisms and preliminary data indicate that ETC inhibitors attenuates hypoxia in the BM of MM patients and increase the efficacy of anti- ICP/ICP-L mAbs (107).

These data confirm that the ICP/ICP-L circuitry is an attractive candidate to combine with HIF-1 inhibitors. Hypoxia increases the number of PD-L1+ MDSC and Tregs in the TME, and targeting hypoxia-driven MCP can prevent the accumulation of these immune suppressive cells (111). The interactions between hypoxia-driven MCP and ICP/ICP-L can also be mediated by exosomes. Interestingly, it has been reported in oral squamous cell carcinoma that exosomes derived from normoxic tumors expand immunocompetent γδ T cells (mainly represented by Vγ9Vδ2 T cells), whereas exosomes derived from hypoxic tumors expand PD-L1+ MDSC that recruit PD1+ anergic γδ T cells (112). This work demonstrates that oxygen pressure in the TME regulates the induction of anti- or pro-tumoral γδ T cells by modulating the release of exosomes by tumor cells.

HIF-1β, a transcription factor steadily translocated in the nucleus to activate the transcriptional program mediated by HIF-1α in hypoxia, is a strong inducer of ABCA1 which is highly expressed in hypoxic endothelial cells (113) and macrophages (114). BMSC of MM patients, deep-rooted in a constitutively hypoxic TME, display high levels of ABCA1 and extrude huge IPP amounts in the TME (49). We are currently investigating whether these unnatural IPP concentrations (in the micromolar range) determine a functional exhaustion of Vγ9Vδ2 T cells by increasing, in the absence of appropriate co-stimulatory signals, the expression of multiple ICP (PD-1, TIM3, LAG-3) (47, 5, 49, 7). We have initiated to investigate whether HIF-1 inhibitors can rescue the immune competence of Vγ9Vδ2 T cells in the TME of MM patients by decreasing ABCA1 expression and extracellular IPP release from BMSC. As said above, metabolic corrections are often double-edged approaches. In this case, decreasing the HIF-1/ABCA1 axis in BMSC may limit the long-term and uncontrolled exposure of BM Vγ9Vδ2 T cells to supra-physiological IPP concentrations and relieve their anergy and senescence, but the down-regulation of IPP production and release by DC may concurrently restrain the activation of Vγ9Vδ2 T cells. In-depth investigation of different expression of cell surface antigens by BMSC vs DC, coupled with medicinal chemistry approaches to conjugate HIF-1 inhibitors with ligands specific for immune suppressive cells, are current under investigation to successfully introduce HIF-1 inhibitors in the clinical setting.

Interestingly, metformin, an anti-diabetic drug that inhibits OXPHO, reduces oxygen consumption in the TME and improves oxygen concentrations (115, 116). The reduced hypoxia relieves several immune suppressive features and increases the efficacy of PD-1 blockade. Metformin alone does not have a significant antitumor activity, but in combination with anti-PD-1 mAb locally increases the number and function of CD8+ cells with antitumor activity (i.e. producing TNF-α and IFN-γ) (107). It is currently unknown the impact of metformin or other hypoxia-targeted treatments on Vγ9Vδ2 T cells under normoxic or hypoxic conditions. Nevertheless, since Vγ9Vδ2 T cells are highly sensitive to the metabolic TME alterations, including hypoxia, it is very likely that remodeling the hypoxic tone in the TME of MM patients is immunologically beneficial also to Vγ9Vδ2 T cells. Besides relieving hypoxia, metformin can be particularly useful in MM patients because it consistently decreases IL-6R expression in myeloma cells (117). IL-6 can promote, in combination with TGF-β and other cytokines highly abundant in the TME of MM patients, the differentiation of IL-17 producing γδ T cells which support tumor cell progression by promoting angiogenesis (118).

Lastly, hypoxia is considered a strong protumoral metabolic change in the TME because it favours the emergence of MDR (119). However, recent data suggest that hypoxia can be exploited to induce the selective activation of prodrugs in the TME. For instance, evofosfamide is a prodrug of the DNA alkylator bromo-isophosphoramide that is activated under hypoxic conditions. environment. Evofosfamide in combination with bortezomib and dexamethasone has shown a safe profile and clinical efficacy in patients with relapsed MM who have failed standard treatments (120).

7.4. Combination with Mev pathway inhibitors

ICP/ICP-L blockade can also be combined with Mev pathway manipulation to improve antitumor immune responses. Promising data have been generated in murine cancer models where inhibition of acetyl citrate lyase (ACLY), the main generator of cytosolic acetylCoA used in cholesterol synthesis, enhances the pro-immunogenic effects of chemotherapy and the efficacy of antitumor T cells. The inhibition of acetylCoA acetyltransferase-1 (ACAT1) that promotes a feedback inhibition of Mev pathway by preventing the esterification of cholesterol, produces similar effects (121, 122). These two metabolic modifications can be used in association with ICP/ICP-L blockade to boost the antimyeloma activity of Vγ9Vδ2 T cells.

Modulation of the Mev pathway can take advantage of the hypoxic TME of MM patients. HMGCR is down-regulated by hypoxia. Direct inhibitors of HMGCR like statins or down-stream FPPS inhibitors like NBP are more cytotoxic against cancer cell lines under hypoxic than normoxic conditions (123). One possible explanation is that the deeper Mev pathway inhibition leads to a drastic intracellular deprivation of cholesterol and isoprenoids that myeloma cells cannot tolerate under hypoxic conditions. Another mechanism can be the BTN3A1 conformational changes induced by NBP-induced intracellular IPP accumulation cells that can increase myeloma cell recognition by Vγ9Vδ2 T cells. The first mechanism may explain why statins and compounds like brutieridin and melitidin, that incorportate the HMG moiety (124), may have potent antitumor effects (125-127) even if they do not induce IPP accumulation and stimulate Vγ9Vδ2 T cells (5, 47, 128). Since lipohilic statins inhibit HIF-1α activity in solid tumors, it is worth investigating whether these drugs can also suppress PD-1L transcription. So far, no data are available about the capacity of statins to inhibit HIF-1α activation in tumor-infiltrating lymphocytes and/or Vγ9Vδ2 T cells. Future research in this field may help to understand whether the combination of lipophilic statins and ICP/ICP-L blockade may enhance antitumor immune responses in the TME of MM patients and eliminate residual MDR+ myeloma cells nested in the hypoxic BM niches.

7.5. Combination with modulators of fatty acid metabolism

Beside the Mev pathway, other lipid metabolic pathways are important mediators of antitumor immune responses and therefore potentially druggable MCP. Any modifications in cellular lipid metabolism significantly affects T-cell fate and function (129). Indeed, the activation-induced proliferation and differentiation of effector T cells is supported by FAS, whereas the development of CD8+ T cell memory cells requires FAO (130, 131). As a consequence, long-lasting memory-like T-cells rely preferentially on mitochondrial OXPHOS and FAO for meeting their energetic demands (130, 132).

Enhanced FA utilization can be an important metabolic opportunity for exhausted T cells that are highly dependent on FAO to support their energetic needs. In the presence of glucose deprivation, FAO becomes the main fueling pathway to preserve the effector functions of CD8+ T cells in the TME. Fenofibrate, a PPAR-α activator with the capacity to increase FAO, sustains the immune competence of CD8+ TIL and delays their functional exhaustion irrespective of PD-1 expression. Interestingly, fenofibrate has been reported to synergize with anti-PD-1 blockade in melanoma (133). Similarly, chemical agents enhancing OXPHOS in CD8+ TIL increase the efficacy of anti-PD1 treatments in colon cancer models (134). These data suggest that increasing FAO and OXPHOS in TIL, in combination with anti-ICP/ICP-L treatment, can represent a significant advance in preventing the functional exhaustion of TIL in the TME. Unfortunately, increasing FAO in T cells may induce unwanted effects on the delicate balance between activation and inhibition of immune cells. FAO is also the main energetic pathway used by Treg cells and MDSC (135-137) to differentiate and exert their immune suppressive activity on T cells. As a consequence, FAO inhibition can prevent Treg accumulation, but it impairs effector T-cell functions; contrariwise, FAO up-regulation can improve T-cell functions, but it increases immunosuppressive functions by Treg cells and MDSC (135).

Lipid metabolism can play a special role in BM-located malignancies like MM. The proportion of BM adipocytes increases with age and therefore it is not surprising that these cells are particularly abundant in the BM of MM patients which is a disease of the older population. Adipocytes in the TME of MM patients can provide FA and triglycerides to myeloma cells (138) that are strategically equipped with appropriate receptors like CD36 and the FA Transporter Proteins (FATPs) to internalize these invaluable energy sources (139, 140). Etomoxir has been used to deprive myeloma cells of FA via inhibition of carnitine palimtoyl transferase 1 (CPT1), the pace-maker enzyme in FAO, yielding to a significant suppression of myeloma cell proliferation (140). Myeloma cells can also produce FA via FAS and this pathway is instrumental to metabolically support their survival and expansion. Interestingly, the combination of etomoxir with orlistat (a FAS inhibitor) synergistically suppresses myeloma cell growth and enhances the sensitivity to bortezomib treatment (141). Although promising, these findings should be regarded with caution because the results have been generated using myeloma cell cultures taken out of the immune suppressive TME.

Very little data are available about lipid metabolism in Vγ9Vδ2 T cells. Recently, it has been shown that IL-21 reduces aerobic glycolysis and increases FAO in T cells. This metabolic reset is paralleled by increased mitochondrial biogenesis to generate long-lasting memory T cells with low PD-1 expression (142). Interestingly, normal Vγ9Vδ2 T cells have enhanced antitumor activity if expanded in the presence of IL-21 and IL-2, whereas Vγ9Vδ2 T cells from cancer patients have defective reactivity to IL-21 stimulation (143). Vγ9Vδ2 T cells from patients with acute myeloid leukemia display lower expression of IL-21R and require higher levels of IL-21 for their expansion. These cells also express significantly higher TIM-3 levels than healthy Vγ9Vδ2 T cells and up-regulate TIM-3 after IL-21 stimulation. Blocking TIM-3 increases the proliferation and reactivity of Vγ9Vδ2 T cells to IL-21 stimulation (144). These data indicate the existence of druggable interconnections between ICP/ICP-L and FA metabolism mediated by cytokines like IL-21. Preliminary data in our laboratory indicate that anergic Vγ9Vδ2 T cells isolated from the TME of MM patients may up-regulate multiple ICP when stimulate by ZA-treated DC in the presence of IL-2. Altogether, these data confirm the multifaceted reactivity of Vγ9Vδ2 T cells embedded in the TME and how their functional plasticity dangerously allows them to switch from antitumoral to protumoral functions (145).

7.6. Combination with IDO inhibitors

IDO inhibition is under investigation as a druggable MCP to improve the efficacy of ICP/ICP-L inhibition. IDO inhibitors can rescue dysfunctional or exhausted T cells by raising tryptophan levels in the TME. L-methyl-tryptophan (1-MT) (146) and INCB024360 (147) have been shown to improve the immune responses of tumor-specific T cells in mouse models. Following these initial observations, indoximod (IDO1 and IDO2 inhibitor), navoximod (IDO1 inhibitor, also known as GDC-0919 and NLG919) and the dual IDO1–TDO inhibitors HTI-1090 (IDO1-TDO inhibitor) also known as SHR9146) and DN1406131 have been developed and investigated as single agents or in combination with ICP/ICP-L blockade (148). Holmgaard et al. have shown that IDO inhibition in combination with CTLA-4, PD-1/PD-L1, and GITR blockade has synergistic activity on tumor cell growth and improves the survival in different tumor models (149). Based on these promising results, clinical trials are currently underway to investigate the combination of anti–CTLA-4 mAb and IDO inhibition in patients with melanoma. The very potent and highly selective IDO1 inhibitor epacadostat (INCB024360) is under clinical investigation as single agent in various advanced-stage malignancies and under consideration in combination with anti-ICP/ICP-L mAbs.

The combination of IDO inhibitors and ICP/ICP-L blockade is also worth investigating in in MM given the well-known role played by in the TME of these patients. A preclinical rationale has been provided by An et al. who have shown that anti-PD-L1 mAb in combination with IDO inhibition can overcome the osteoclast-induced suppression of T-cell mediated antimyeloma immune responses (150). IDO inhibition can also alleviate Vγ9Vδ2 T-cell immunosuppression induced by the overproduction of kynurenines by myeloma cells and MDSC in the TME.

7.7. Combination with Arg1 inhibitors

Arginine deprivation is another major MCP restraining antitumor immune responses mediated by T cells and NK cells in the TME (151). Arginine supply and/or prevention of arginine degradation via Arg1 inhibition are feasible strategies to reinstate antitumor immune responses in the TME. As expected, arginine supplementation revives the cytotoxic functions of T cells and NK cells, and, in combination with anti-PD-L1 mAb, enhances antitumor immune responses and prolongs the survival of tumor-bearing mice (152). CB-1158, a potent and orally-bioavailable small-molecule Arg1 inhibitor, has shown efficacy in murine syngeneic tumor models (153) as single agent or in triple combination with adoptive T-cell or NK-cell therapy, adoptive NK cell therapy, and anti-PD-L1 mAb. The combination of CB-1158 and anti-PD-L1 mAb is currently under clinical investigation in patients with advanced/metastatic solid tumors (NCT02903914, INCB 01158-10) (154).

Interestingly, arginine metabolism can also be modulated in the TME by targeting its conversion into citrulline. In the presence of arginine deprivation, normal tissues can increase citrulline uptake and up-regulate the expression of argininosuccinate synthetase 1 (ASS1) which converts citrulline into arginine. This auxotrophy mechanism can be defective in tumor cells that are unable to up-regulate or lack ASS1 (155). Pegylated arginine deiminase (ADI-PEG 20) has been develop to convert arginine into citrulline and ammonia, making ASS1-deficient tumor cells unable to use citrulline to generate arginine and meet their metabolic needs (156). ADI-PEG 20 has shown antitumor activity in ASS1-deficient tumor cells from patients with breast cancer (157), small-cell lung cancer (158) and acute myeloid leukemia (159). Interestingly, T cells can increase citrulline uptake and up-regulate ASS1 expression under low arginine conditions (160-162). Thus, the conversion of arginine into citrulline by ADI-PEG 20 may have different effects on T cells compared with arginine depletion induced by Arg1. Indeed, Brin et al. have shown that peripheral blood T cells from healthy donors can be fully activated in the presence of ADI-PEG 20 avoiding PD-1 up-regulation and the differentiation into Treg cells. In murine syngeneic tumor models, ADI-PEG 20 has been reported to promote the recruitment of T cells in the TME and improve the efficacy of anti-PD-L1 treatment (163).

Targeting Arg1 can also be effective in MM. We have shown that PD-L1+ MDSC are significantly expanded in the TME of MGUS and MM patients, irrespective of the percentage of TME-infiltrating myeloma cells (5). Romano A. et al. have recently shown that Arg-1 is highly expressed by MDSC of MM patients (164). Arg-1 inhibition improves the in vitro antimyeloma activity of bortezomib and lenalidomide and this combination is currently tested in animal models to determine safety and efficacy in vivo. We are currently investigating whether Arg-1 up-regulation and arginine deprivation are involved in the dysfunction of BM Vγ9Vδ2 T cells in MGUS and MM patients.

Borrello’s group has pursued a different strategy to target the immune suppressive functions of MDSC in the TME of MM patient (165). They have shown that sildenafil down-regulates Arg1 and nitric oxide synthase–2 (NOS2) expression, thereby reducing the suppressor function of MDSC and ameliorating antimyeloma immune responses mediated by T cells. In the clinical setting, they have shown that tadalafil, another phosphodiesterase-5 (PDE5) inhibitor, attenuates the suppressor functions of MDSC and allows the achievement of measurable antimyeloma immune responses (166). When added to chemotherapy, this approach has improved the clinical outcome of end-stage relapsed/refractory MM. We have investigated the effects of PDE5 inhibitor sildenafil on pAg-reactivity of BM Vγ9Vδ2 T cells from MM patients and failed to show any functional recovery, further confirming the deeper impairment of these cells compared with conventional T cells (5).

MDSC also express high levels of NOS2, which convert arginine into NO. NO can suppresses T-cell function either by S‑nitrosylation of critical cysteine protein residues or by regulation of guanylyl cyclase and cyclic GMP-dependent kinases (167). Sharing the same substrate, NOS2 and Arg-1 are in dynamic competition with the former having much higher affinity for arginine, but much slower catalytic activity. In the presence of severe arginine depletion, NOS2 switches from arginine degradation to the generation of reactive oxygen species (ROS) and reactive nitrogen species which are immune suppressor metabolites. These data suggest that the combination of Arg1 and NOS2 inhibitors should ensure the most effective MDSC inhibition. NCX‑4016 (nitroaspirin), a small molecule developed to test this hypothesis, has been shown to correct the immune dysfunction and promotes tumor eradication after cancer vaccination in tumor-bearing mice (168).

Targeting NOS2 could be particularly rewarding to rescue the immunocompetence of Vγ9Vδ2 T cells. Douguet et al. have shown that a significant proportion of γδ T cells infiltrating mouse and human melanoma express NOS2. Experimental data in the murine melanoma model indicate that NOS2 can be involved in the generation and expansion of IL-17-producers tumor-promoting γδ T cells which, in turn, can promote the recruitment and accumulation of MDSC in the TME (169). It is currently unknown whether NOS2 is also expressed by BM Vγ9Vδ2 T cells from other cancers, but the combination of NOS2 inhibitors and ICP/ICP-L blockade sounds very interesting to recruit immune effector cells, including Vγ9Vδ2 T cells, in the TME of MGUS and MM patients.

7.8. Targeting glutamine uptake and glutamine metabolism

Glutamine metabolism is critical for tumor cell survival and therefore another attractive MCP to target for therapeutic interventions. The whole pathway has been considered and several compounds developed, from glutamine analogs to inhibitors of glutamine transporters or inhibitors of glutamate conversion to α‑ketoglutarate (170). Some of these compounds have moved on to clinical trials as single agents or in association with anti-ICP/ICP-L mAbs (148).

The importance of glutamine metabolism in myeloma cells have arisen from the clinical observation that a significant proportion of MM patients at diagnosis are affected by hyperammonemia and encephalopathy in the absence of liver dysfunction. Subsequently, it has been shown that human myeloma cell lines and primary myeloma cells, lacking a detectable expression of glutamine synthetase (GS), rely on the uptake of extracellular glutamine, mainly via the ASCT2 glutamine transporter, for their growth and survival. Bolzoni et al have shown that blocking glutamine uptake significantly affects the viability of myeloma cells and their sensitivity to bortezomib and other drugs. They have also shown that stable ASCT2 downregulation by a lentiviral approach inhibits the growth of human myeloma cell in vitro and in a murine model. Similar data have been reported using the combination of glutaminase (GLS) inhibitor CB-839 alone or in combination with pomalidomide (171, 172) or glutamine deprivation in the presence of venetoclax (173).

Targeting glutamine metabolism in myeloma cells may have many-sided effects on T cells in the TME. Glutamine uptake and glutaminolysis are up-regulated in naïve T cells after activation to support their proliferation (62). Following activation, glutamine levels can regulate the functional differentiation of specific CD4+ and CD8+ subsets. In the presence of adequate glutamine supply, effector T cells can shift from glycolysis to OXPHOS to generate central memory-like cells with enhanced survival and antitumor activity (71). In the presence of glutamine deprivation, including ASCT2 deletion, T-cell activation results in the differentiation into Foxp3+ Tregs cells that further suppress T-cell activity (70). More recently, it has been shown that inhibition of glutaminolysis at the level of GLS can have different effects on T-cell differentiation compared to depletion of extracellular sources. Johnson et al have shown that GLS promotes the functional differentiation of Th17 cells in spite of Th1 cells. Transient GLS inhibition leads to increased Th1 differentiation and the generation of CD8+ CTL effector functions (174). It is currently unknown whether glutamine metabolism, either as deprivation of external source or as impaired GLS activity, may impact on the functional differentiation of Vγ9Vδ2 T-cell subsets. Interestingly, IL-17-producing γδ T cells have been reported to be generated in the TME of tumor-bearing mouse and to behave as tumor-promoting cells (175). We are currently investigating whether the glutamine deprivation induced by myeloma cells in the TME in the presence of IL-6 and TGF-β promotes the generation of IL-17-producing Vγ9Vδ2 T cells as in tumor-bearing mice.

Given the strong impact that manipulation of glutamine metabolism may have on antitumor immune responses, it is not suprising that clinical trials are under investigation in combination with anti-ICP/ICP-L mAbs. Trigriluzole (BHV-4157), a compound that reduces extracellular glutamate levels, is currently tested in combination with nivolumab or pembrolizumab in metastatic or unresectable solid tumors or lymphoma (NCT03229278), while CB-839 (glutaminase 1 inhibitor) is tested in combination with nivolumab in advanced- stage clear cell renal carcinoma, melanoma and non small cell lung cancer (NCT02771626) (148).

7.9. Combination with ADO pathway inhibitors

Ado is an important MCP in the hypoxic BM niche where residual myeloma cells can survive chemotherapy and immunotherapy (176). Ado, through its receptor A2AR, can up-regulate PD-1 expression on CD8+ and Treg cells (177) and the dual blockade of PD-1 and A2AR synergistically increases the cytotoxic potential of CD8+ cells and controls tumor growth (178). Combination of A2AR inhibition with TIM-3 or CTLA-4 blockade has also been shown to be effective in enhancing antitumor immune responses in a variety of syngeneic tumor models (179).

The role of Ado in the immune suppressive TME of MM patients is also under investigation (180). Yang R et al. have reported increased Ado concentration in the BM plasma from MM patients compared with healthy controls (181). CD39 expression by myeloma cells coupled with CD73 expression by BMSC and other bystander cells are responsible for the generation of immunosuppressive extracellular Ado concentrations in the TME leading to A2AR-mediated T-cell inhibition. The CD39 inhibitor POM1 inhibits Ado generation in myeloma cell/BMSC co-cultures and restores T-cell proliferation in vitro. Interestingly, high CD39 expression in the TME of MM patients confers a poor clinical outcome further supporting the role Ado in the immunosuppressive TME of these patients (181). Richles RJ et al. have shown that A2AR agonists in combination with PDE inhibitors act synergistically in triple combination with glucocorticoid to suppress the proliferation of myeloma cells in vitro (182).

Extracellular Ado in the TME of MM patients can also be generated from nicotinamide dinucleotide (NAD) by the concerted action of CD38, CD203a and CD73 (183). CD38 is a multifunctional ecto-enzyme acting also as a receptor and adhesion molecule in the TME of MM patients. Being expressed by myeloma cells and several other lymphoid and myeloid cells in the TME, CD38 is strategically located as a target intersection to modulate tumor-host interactions (184). Several anti-CD38 mAb like daratumumab, isatuximab, and MOR202 have been developed and clinically used in MM patients as single agents or in combination with steroids and other drugs (185). Although several cell subsets express both CD38 and ICP/ICP-L in the TME of MM patients (including myeloma cells, immune suppressor cells and immune effector cells), very little data are available about the cascade of reciprocal interactions eventually triggered by anti-CD38 or anti-ICP/ICP-L mAbs. Chen et al. have reported in lung cancer and animal models that acquired resistance to anti-PD-1/PD-L1 mAbs is mediated by CD38 upregulation and shown that concurrent CD38 and PD-1/PD-L1 inhibition improves antitumor immune responses (186).

The role of Ado pathway in γδ T-cell functions is much less recognized. Liang D. et al. have addressed this issue in an experimental autoimmune uveitis mouse model (187). They have shown that the CD73 and A2AR expression on γδ T cells are dependent on their activation status and modulate immune responses mediated by Th17 and Treg cells by fine-tuning extracellular Ado concentration (188, 189). CD73 and CD39 expression has been correlated with the acquisition of suppressor functions in Vγ9Vδ2 T cells after exposure to pAg in the presence of inappropriate cytokines (190, 191). CD39 upregulation has been reported to dephosphorylate self and microbial pAgs restraining the reactivity of Vγ9Vδ2 T cells (192).


The TME of MM patients is affected by a metabolic reset orchestrated by myeloma cells when their number exceeds the physiological threshold (2-3%) that the BM is well-suited to accommodate. The metabolic reset is finalized to sustain myeloma cell growth and promote resistance to chemotherapy and immunosurveillance. Hypoxia, low pH, nutrients deprivation, and toxic waste compromise the antimyeloma activity of immune effector cells (CD8+ cells, NK cells, Vγ9Vδ2 T cells, etc) and drive the differentiation of immune suppressor cells (Tregs, MDSC, M2 macrophages, etc). Vγ9Vδ2 T cells are among the first immune effector cells to fall prey to the immune suppressive TME elaborated by myeloma cells. The expression of ICP/ICP-L is facilitated by metabolic alterations and this deadly network makes very challenging to rescue the immunocompetence of Vγ9Vδ2 T cells and other immune effector cells.

A growing body of evidence indicates that targeting MCP in combination with ICP/ICP-L blockade is a strategy that can significantly improve the efficacy of immunotherapy. This strategy can be applied ex-vivo using metabolic correctors in adoptive immunotherapy trials to make immune cells more resistant to the metabolic challenges encountered upon reinfusion. Alternatively, metabolic correctors could be used in vivo in association with ICP/ICP-L blockade in the remission phase when most of myeloma cells have been eliminated by chemotherapy. This approach is feasible in disease like MM where current treatments based on the combination of autologous stem cell transplantation (ASCT) with novel drugs can achieve complete remission with undetectable minimal residual disease in a significant proportion of patients. We have shown that the immune suppressive TME imprinting is not reversed in MM who are in complete remission after ASCT. This can represent a privileged setting for immune interventions because metabolic correctors and ICP/ICP-L blockade are expected to target mainly immune cells and, in the absence of myeloma cells, to restore effective and long-lasting immunosurveillance.


This study was supported by the Italian Association for Cancer Research (AIRC) (IG15232 and IG21408 to CR; IG16985 and IG21744 to MM). B.C. is a post-doc research fellow supported by AIRC.

E Lo Presti G Pizzolato E Gulotta G Cocorullo G Gulotta F Dieli S Meraviglia Current Advances in γδ T Cell-Based Tumor Immunotherapy. Front Immunol. 2017 27 8 1401 DOI: 10.3389/fimmu.2017.01401
B Castella C Vitale M Coscia M Massaia Vc9Vd2 T cell-based immunotherapy in hematological malignancies: from bench to bedside. Cell. Mol. Life Sci. 2011 68 2419 2432 DOI: 10.1007/s00018-011-0704-8
M Burjanadzé M Condomines T Reme P Quittet P Latry C Lugagne F Romagne Y Morel JF Rossi B Klein ZY Lu In vitro expansion of gamma delta T cells with antimyeloma cell activity by Phosphostim and IL-2 in patients with multiple myeloma. Br J Haematol. 2007 139 2 206 16 DOI: 10.1111/j.1365-2141.2007.06754.x
M Wilhelm V Kunzmann S Eckstein P Reimer F Weissinger T Ruediger HP Tony γδ T cells for immune therapy of patients with lymphoid malignancies. Blood 2003 102 1 200 6 DOI: 10.1182/blood-2002-12-3665
B Castella M Foglietta P Sciancalepore M Rigoni M Coscia V Griggio C Vitale R Ferracini E Saraci P Omedé C Riganti A Palumbo M Boccadoro M Massaia Anergic bone marrow Vγ9Vδ2 T cells as early and long-lasting markers of PD-1-targetable microenvironment-induced immune suppression in human myeloma. Oncoimmunology. 2015 4 11 e1047580 DOI: 10.1080/2162402X.2015.1047580
B Castella M Foglietta C Riganti M Massaia Vγ9Vδ2 T Cells in the Bone Marrow of Myeloma Patients: A Paradigm of Microenvironment-Induced Immune Suppression. Front Immunol. 2018 225 9 1492 DOI: 10.3389/fimmu.2018.01492
B Castella A Melaccio M Foglietta C Riganti M Massaia Vγ9Vδ2 T Cells as Strategic Weapons to Improve the Potency of Immune Checkpoint Blockade and Immune Interventions in Human Myeloma. Front Oncol. 2018 8 508 DOI: 10.3389/fonc.2018.00508
AM Lesokhin SM Ansell P Armand EC Scott A Halwani M Gutierrez MM Millenson AD Cohen SJ Schuster D Lebovic M Dhodapkar D Avigan B Chapuy AH Ligon GJ Freeman SJ Rodig D Cattry L Zhu JF Grosso MB Bradley Garelik MA Shipp I Borrello J Timmerman Nivolumab in patients with relapsed or refractory hematologicmalignancy: preliminary results of a phase Ib study. J Clin Oncol. 2016 34 23 2698 704 DOI: 10.1200/JCO.2015.65.9789
J1 Rosenblatt myeloma Avigan D1. Targeting the PD-1/PD-L1 axis in multiple a dream or a reality? Blood. 2017 129 3 275 279 DOI: 10.1182/blood-2016-08-731885
KG Anderson IM Stromnes PD Greenberg Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies. Cancer Cell. 2017 31 3 311 325 DOI: 10.1016/j.ccell.2017.02.008
R Ramapriyan MS Caetano HB Barsoumian ACP Mafra EP Zambalde H Menon E Tsouko JW Welsh MA Cortez Altered cancer metabolism in mechanisms of immunotherapy resistance. Pharmacol Ther. 2019 195 162 17 DOI: 10.1016/j.pharmthera.2018.11.004
P Sharma JP Allison Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015 61 2 205 14 DOI: 10.1016/j.cell.2015.03.030
S Lim JB Phillips L Madeira da Silva M Zhou O Fodstad LB Owen M Tan Interplay between Immune Checkpoint Proteins and Cellular Metabolism. Cancer Res. 2017 77 6 1245 1249 DOI: 10.1158/0008-5472.CAN-16-1647
C El Arfani K De Veirman K Maes E De Bruyne E Menu Metabolic Features of Multiple Myeloma Int. J. Mol. Sci. 19 2018 1200 DOI: 10.3390/ijms19041200
D Rizzieri B Paul Y Kang Metabolic alterations and the potential for targeting metabolic pathways in the treatment of multiple myeloma. J Cancer Metastasis Treat. 2019 5 pii 26 DOI: 10.20517/2394-4722.2019.05
N Steiner U Mueller R Hajek S Sevcikova B Borjan K JoÈhrer G Göbel A Pircher E Gunsilius The metabolomic plasma profile of myeloma patients is considerably different from healthy subjects and reveals potential new therapeutic targets. PLoS ONE 2018 13 8 e0202045 DOI: 10.1371/journal.pone.0202045
A Nakano H Miki S Nakamura T Harada A Oda H Amou S Fujii K Kagawa K Takeuchi S Ozaki T Matsumoto M Abe Up-regulation of hexokinaseII in myeloma cells: Targeting myeloma cells with 3-bromopyruvate J. Bioenerg. Biomembr 2012 44 31 38 DOI: 10.1007/s10863-012-9412-9
Z Gu J Xia H Xu I Frech G Tricot F Zhan NEK2 Promotes Aerobic Glycolysis in Multiple Myeloma Through Regulating Splicing of Pyruvate Kinase. J Hematol Oncol. 2017 10 1 17 DOI: 10.1186/s13045-017-0392-4
Fujiwara Shiho Kawano Yawara Yuki Hiromichi Okuno Yutaka Nosaka Kisato Mitsuya Hiroaki Glycolysis Hiroyuki Hata. Aerobic A Possible Target for Treating Multiple Myeloma (MM) with High Serum LDH Levels. Blood 2011 118 1799
N Giuliani M Chiu M Bolzoni F Accardi MG Bianchi D Toscani F Aversa O Bussolati The potential of inhibiting glutamine uptake as a therapeutic target for multiple myeloma. Expert Opin Ther Targets. 2017 21 3 231 234 DOI: 10.1080/14728222.2017.1279148
C Corbet O Feron Metabolic and mind shifts: from glucose to glutamine and acetate addictions in cancer. Curr Opin Clin Nutr Metab Care. 2015 18 346 353 DOI: 10.1097/MCO.0000000000000178
M Bolzoni M Chiu F Accardi R Vescovini I Airoldi P Storti K Todoerti L Agnelli G Missale R Andreoli MG Bianchi M Allegri A Barilli F Nicolini A Cavalli F Costa V Marchica D Toscani C Mancini E Martella V Dall'Asta G Donofrio F Aversa O Bussolati N Giuliani Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: A new attractive target Blood 128 2016 667 679 DOI: 10.1182/blood-2016-01-690743
S Kouidhi F Ben Ayed A Benammar Elgaaied Targeting Tumor Metabolism: A New Challenge to Improve Immunotherapy Front. Immunol. 9 2018 353 DOI: 10.3389/fimmu.2018.00353
Beckermann K.E. Dudzinski S.O. Rathmell J.C Dysfunctional T Rathmell, J.C: Dysfunctional T cell metabolism in the tumor microenvironment. Cytokine Growth Factor Rev. 2017 35 7 14 DOI: 10.1016/j.cytogfr.2017.04.003
G Noël ML Fontsa K Willard-Gallo The impact of tumor cell metabolism on T cell-mediated immune responses and immuno-metabolic biomarkers in cancer. Semin. Cancer Biol. 2018 1 28 DOI: 10.1016/j.semcancer.2018.03.003
JS Harrison P Rameshwar V Chang P Bandari Oxygen saturation in the bone marrow of healthy volunteers Blood 99 2002 394 394 DOI: 10.1182/blood.V99.1.394
S Colla P Storti G Donofrio K Todoerti M Bolzoni M Lazzaretti M Abeltino L Ippolito A Neri D Ribatti V Rizzoli E Martella N Giuliani Low bone marrow oxygen tension and hypoxia-inducible factor-1 alpha overexpression characterize patients with multiple myeloma: role on the transcriptional and proangiogenic profiles of CD138(+) cells Leukemia 21010 24 1967 1970 DOI: 10.1038/leu.2010.193
Martin S.K Diamond P P.Gronthos S Peet D Zannettino A.C The emerging role of hypoxia, HIF-1 and HIF-2 in multiple myeloma Leukemia 2011 25 1533 1542 DOI: 10.1038/leu.2011.122
K Asosingh H De Raeve M de Ridder GA Storme A Willems I Van Riet B Van Camp K Vanderkerken Role of the hypoxic bone marrow microenvironment in 5T2MM murine myeloma tumor progression. Haematologica 2005 90 810 817
J Hu DR Handisides E Van Valckenborgh H De Raeve E Menu I Vande Broek Q Liu JD Sun B Van Camp CP Hart K Vanderkerken Targeting the multiple myeloma hypoxic niche with TH-302, a hypoxia-activated prodrug. Blood 2010 116 9 1524 7 DOI: 10.1182/blood-2010-02-269126
AK Azab J Hu P Quang F Azab C Pitsillides R Awwad B Thompson P Maiso JD Sun CP Hart AM Roccaro A Sacco HT Ngo CP Lin AL Kung RD Carrasco K Vanderkerken IM Ghobrial Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition like features. Blood. 2012 119 24 5782 94 DOI: 10.1182/blood-2011-09-380410
I Filippi I Saltarella C Aldinucci F Carraro R Ria A Vacca A Naldini Different Adaptive Responses to Hypoxia in Normal and Multiple Myeloma Endothelial Cells Cell Physiol Biochem 2018 46 203 212 DOI: 10.1159/000488423
A Bhaskar BN Tiwary Hypoxia inducible factor-1 alpha and multiple myeloma Int J Adv Res (Indore) 2016 4 706 715
P Maiso D Huynh M Moschetta A Sacco Y Aljawai Y Mishima JM Asara AM Roccaro AC Kimmelman IM Ghobrial Metabolic signature identifies novel targets for drug resistance in Multiple Myeloma Cancer Res. 75 2015 2071 2082 DOI: 10.1158/0008-5472.CAN-14-3400
KA Zub MM Sousa A Sarno A Sharma A Demirovic S Rao C Young PA Aas I Ericsson A Sundan ON Jensen G Slupphaug Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells. PLoS One. 2015 10 3 e0119857 DOI: 10.1371/journal.pone.0119857
Hu J Van Valckenborgh E Menu E De Bruyne E Vanderkerken K (2012) Understanding the hypoxic niche of multiple myeloma: therapeutic implications and contributions of mouse models Dis Model Mech 2012 5 763 771 20 DOI: 10.1242/dmm.008961
RM Thompson D Dytfeld L Reyes RM Robinson B Smith Y Manevich A Jakubowiak M Komarnicki A Przybylowicz-Chalecka T Szczepaniak AK Mitra BG Van Ness M Luczak NG Dolloff Glutaminase inhibitor CB-839 synergizes with carfilzomib in resistant multiple myeloma cells Oncotarget 8 2017 35863 35876 DOI: 10.18632/oncotarget.16262
L Janker RL Mayer A Bileck D Kreutz JC Mader K Utpatel D Heudobler H Agis C Gerner A Slany Metabolic, anti-apoptotic and immune evasion strategies of primary human myeloma cells indicate adaptations to hypoxia. Mol Cell Proteomics. 2019 18 5 936 953 DOI: 10.1074/mcp.RA119.001390
H Du L Wang B Liu J Wang H Su T Zhang Z Huang Analysis of the Metabolic Characteristics of Serum Samples in Patients With Multiple Myeloma. Front Pharmacol. 2018 9 884 DOI: 10.3389/fphar.2018.00884
EM Palsson-McDermott L Dyck Z Zasłona D Menon AF McGettrick KHG Mills LA O'Neill Pyruvate Kinase M2 Is Required for the Expression of the Immune Checkpoint PD-L1 in Immune Cells and Tumors. Front Immunol. 2017 8 1300 DOI: 10.3389/fimmu.2017.01300
G Bonanno A Mariotti A Procoli V Folgiero D Natale L De Rosa I Majolino L Novarese A Rocci M Gambella M Ciciarello G Scambia A Palumbo F Locatelli R De Cristofaro S Rutella Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma. J Transl Med. 2012 10 247 DOI: 10.1186/1479-5876-10-247
S Pfeifer M Schreder A Bolomsky S Graffi D Fuchs SS Sahota H Ludwig N Zojer Induction of indoleamine-2,3 dioxygenase in bone marrow stromal cells inhibits myeloma cell growth. J Cancer Res Clin Oncol. 2012 138 11 1821 30 DOI: 10.1007/s00432-012-1259-2
E Vacchelli F Aranda A Eggermont C Sautès-Fridman E Tartour EP Kennedy M Platten L Zitvogel G Kroemer L Galluzzi Trial watch: IDO inhibitors in cancer therapy. Oncoimmunology 2014 3 10 e957994 DOI: 10.4161/21624011.2014.957994
Ellen van der Spek Targeting the mevalonate pathway in multiple myeloma. Leukemia Research 2010 34 267 268 DOI: 10.1016/j.leukres.2009.07.027
Gruenbacher Georg Martin Thurnher Mevalonate metabolism in cancer. Cancer Letters 2015 356 192 196 DOI: 10.1016/j.canlet.2014.01.013
C Riganti B Castella J Kopecka I Campia M Coscia G Pescarmona A Bosia D Ghigo M Massaia Zoledronic acid restores doxorubicin chemosensitivity and immunogenic cell death in multidrug-resistant human cancer cells. PLoS One. 2013 8 4 e60975 DOI: 10.1371/journal.pone.0060975
B Castella C Riganti F Fiore F Pantaleoni ME Canepari S Peola M Foglietta A Palumbo A Bosia M Coscia M Boccadoro M Massaia Immune modulation by zoledronic acid in human myeloma: an advantageous cross-talk between Vγ9Vδ2 T cells, αβ CD8+ T cells, regulatory T cells, and dendritic cells. J Immunol. 2011 187 4 1578 90 DOI: 10.4049/jimmunol.1002514
H Mönkkönen J Kuokkanen I Holen A Evans DV Lefley M Jauhiainen S Auriola J Mönkkönen Bisphosphonate-induced ATP analog formation and its effect on inhibition of cancer cell growth. Anticancer Drugs 2008 19 4 391 9 DOI: 10.1097/CAD.0b013e3282f632bf
B Castella J Kopecka P Sciancalepore G Mandili M Foglietta N Mitro D Caruso F Novelli C Riganti M Massaia The ATP-binding cassette transporter A1 regulates phosphoantigen release and Vγ9Vδ2 T cell activation by dendritic cells. Nat Commun. 2017 8 15663 DOI: 10.1038/ncomms15663
C Riganti B Castella M Massaia ABCA1, apoA-I, and BTN3A1: A Legitimate Ménage à Trois in Dendritic Cells. Front Immunol. 2018 9 1246 DOI: 10.3389/fimmu.2018.01246
NW van de Donk MM Kamphuis HM Lokhorst AC Bloem The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells. Leukemia 2002 16 1362 71 DOI: 10.1038/sj.leu.2402501
N Gronich L Drucker H Shapiro J Radnay S Yarkoni M Lishner Simvastatin induces death of multiple myeloma cell lines. J Invest Med 2004 52 335 44 DOI: 10.1136/jim-52-05-34
AU Ural MI Yilmaz F Avcu A Pekel M Zerman O Nevruz A Sengul A Yalcin The bisphosphonate zoledronic acid induces cytotoxicity in human myeloma cell lines with enhancing effects of dexamethasone and thalidomide. Int J Hematol 2003 78 443 9 DOI: 10.1007/BF02983818
CM Shipman MJ Rogers JF Apperley RG Russell PI Croucher Bisphosphonates induce apoptosis in humanmyeloma cell lines: a novel anti-tumour activity. Br J Haematol 1997 98 665 72 DOI: 10.1046/j.1365-2141.1997.2713086.x
T Minegaki S Koiki Y Douke C Yamane A Suzuki M Mori M Tsujimoto K Nishiguchi Augmentation of the cytotoxic effects of nitrogen-containing bisphosphonates in hypoxia. J Pharm Pharmacol. 2018 70 8 1040 1047 DOI: 10.1111/jphp.12934
IC Salaroglio I Campia J Kopecka E Gazzano S Orecchia D Ghigo C Riganti Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma. Oncotarget. 2015 6 2 1128 42 DOI: 10.18632/oncotarget.2731
E van der Spek AC Bloem HM Lokhorst B van Kessel L Bogers-Boer NW van de Donk Inhibition of the mevalonate pathway potentiates the effects of lenalidomide in myeloma. Leuk Res. 2009 33 1 100 8 DOI: 10.1016/j.leukres.2008.06.001
S Mariani M Muraro F Pantaleoni F Fiore B Nuschak S Peola M Foglietta A Palumbo M Coscia B Castella B Bruno R Bertieri L Boano M Boccadoro M Massaia Effector gammadelta T cells and tumor cells as immune targets of zoledronic acid in multiple myeloma. Leukemia. 2005 19 4 664 70 DOI: 10.1038/sj.leu.2403693
PC Raemer K Kohl C Watzl Statins inhibit NK-cell cytotoxicity by interfering with LFA-1-mediated conjugate formation. Eur J Immunol. 2009 39 6 1456 65 DOI: 10.1002/eji.200838863
N Zhang M Zhang RT Liu P Zhang CL Yang LT Yue H Li YK Li RS Duan Statins reduce the expressions of Tim-3 on NK cells and NKT cells in atherosclerosis. Eur J Pharmacol. 15; 2017 821 49 56 DOI: 10.1016/j.ejphar.2017.12.050
F Dieli F Poccia M Lipp G Sireci N Caccamo C Di Sano A Salerno Differentiation of effector/memory Vδ2 T cells and migratory routes in lymph nodes or inflammatory sites. J Exp Med 2003 198 391 397 DOI: 10.1084/jem.20030235
NJ MacIver RD Michalek JC Rathmell Metabolic regulation of T lymphocytes. Annu Rev Immunol. 2013 31 259 83 DOI: 10.1146/annurev-immunol-032712-095956
RM1 Laird BJ Wolf MF Princiotta SM Hayes γδ T cells acquire effector fates in the thymus and differentiate into cytokine-producing effectors in a Listeria model of infection independently of CD28 costimulation". PLoS One. 9; 2013 8 5 e63178 DOI: 10.1371/journal.pone.0063178
A Marçais J Cherfils-Vicini C Viant S Degouve S Viel A Fenis J Rabilloud K Mayol A Tavares J Bienvenu YG Gangloff E Gilson E Vivier T Walzer The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat Immunol. 2014 15 8 749 757 DOI: 10.1038/ni.2936
M Swamy S Pathak KM Grzes S Damerow LV Sinclair DM van Aalten DA Cantrell Glucose and glutamine fuel protein O- GlcNAcylation to control T cell self- renewal and malignancy Nat. Immunol. 17 2016 712 720 DOI: 10.1038/ni.3439
RM Loftus N Assmann N Kedia-Mehta KL O'Brien A Garcia C Gillespie JL Hukelmann PJ Oefner AI Lamond CM Gardiner K Dettmer DA Cantrell LV Sinclair DK Finlay Amino acid- dependent cMyc expression is essential for NK cell metabolic and functional responses in mice Nat. Commun. 9 2018 2341 DOI: 10.1038/s41467-018-04719-2
CH Chang J Qiu D O'Sullivan MD Buck T Noguchi JD Curtis Q Chen M Gindin MM Gubin GJ van der Windt E Tonc RD Schreiber EJ Pearce EL Pearce Metabolic competition in the tumor microenvironment is a driver of cancer progression Cell 162 2015 1229 1241 DOI: 10.1016/j.cell.2015.08.016
RP Donnelly RM Loftus SE Keating KT Liou CA Biron CM Gardiner DK Finlay mTORC1-dependent metabolic reprogramming is a prerequisite for NK cell effector function J. Immunol. 193 2014 4477 4484 DOI: 10.4049/jimmunol.1401558
RD Michalek VA Gerriets R Jacobs AN Macintyre N Maciver EF Mason SA Sullivan AG Nichols JC Rathmell Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets J. Immunol. 2011 186 3299 3303 DOI: 10.4049/jimmunol.1003613
D Klysz X Tai PA Robert M Craveiro G Cretenet L Oburoglu C Mongellaz S Floess V Fritz MI Matias C Yong N Surh JC Marie J Huehn V Zimmermann S Kinet V Dardalhon N Taylor Glutamine-dependent alpha-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci Signal. 2015 8 396 ra97 DOI: 10.1126/scisignal.aab2610
R Geiger JC Rieckmann T Wolf C Basso Y Feng T Fuhrer M Kogadeeva P Picotti F Meissner M Mann N Zamboni F Sallusto A Lanzavecchia L-Arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167(3): 2016 829 842.e13 DOI: 10.1016/j.cell.2016.09.031
S S. Ugel F De Sanctis S Mandruzzato V Bronte Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages. J. Clin. Invest. 2015 125 9 3365 3376 DOI: 10.1172/JCI80006
PC1 Rodriguez DG Quiceno AC Ochoa L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 2007 109 4 1568 73 DOI: 10.1182/blood-2006-06-031856
A Sacchi N Tumino A Sabatini E Cimini R1 Casetti V1 Bordoni G1 Grassi C1 Agrati Myeloid-Derived Suppressor Cells Specifically Suppress IFN-γ Production and Antitumor Cytotoxic Activity of Vδ2 T Cells. Front Immunol. 2018 9 1271 DOI: 10.3389/fimmu.2018.01271
E Ananieva Targeting amino acid metabolism in cancer growth and anti-tumor immune response. World J Biol Chem. 2015 6 4 281 9 DOI: 10.4331/wjbc.v6.i4.281
F Fallarino U Grohmann S You BC Mcgrath DR Cavener C Vacca C Orabona R Bianchi ML Belladonna C Volpi P Santamaria MC Fioretti P Puccetti The combined effects of tryptophan starvation and tryptophan catabolites downregulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells J. Immunol. 176 2006 6752 6761 DOI: 10.4049/jimmunol.176.11.6752
KL Hippen RS O'Connor AM Lemire A Saha EA Hanse NC Tennis SC Merkel A Kelekar JL Riley BL Levine CH June LA Turka LS Kean ML MacMillan JS Miller JE Wagner DH Munn BR Blazar In vitro Induction of Human Regulatory T Cells Using Conditions of Low Tryptophan Plus Kynurenines. Am J Transplant 2017 17 12 3098 3113 DOI: 10.1111/ajt.14338
M Foglietta B Castella S Mariani M Coscia L Godio R Ferracini M Ruggeri V Muccio P Omedè A et al. Palumbo The bone marrow of myeloma patients is steadily inhabited by a normal-sized pool of functional regulatory T cells irrespective of the disease status. Haematologica. 2014 99 10 1605 10 DOI: 10.3324/haematol.2014.105866
V Kunzmann B Kimmel T Herrmann H Einsele M Wilhelm Inhibition of phosphoantigen-mediated gammadelta T-cell proliferation by CD4+ CD25+ FoxP3+ regulatory T cells. Immunology. 2009 126 2 256 67 DOI: 10.1111/j.1365-2567.2008.02894.x
K Fechter A Dorronsoro Jakobsson IFNγ Regulates Activated Vδ2+ T Cells through a Feedback Mechanism Mediated by Mesenchymal Stem Cells. PLoS ONE 2017 12 1 e0169362 DOI: 10.1371/journal.pone.0169362
ET Clambey EN McNamee JA Westrich LE Glover EL Campbell P Jedlicka EF de Zoeten JC Cambier KR Stenmark SP Colgan HK Eltzschig Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci U S A 109:E 2012 2784 93 DOI: 10.1073/pnas.1202366109
Y Li SP Patel J Roszik Y Qin Hypoxia-Driven Immunosuppressive Metabolites in the Tumor Microenvironment: New Approaches for Combinational Immunotherapy. Front. Immunol. 2018 9 1591 DOI: 10.3389/fimmu.2018.01591
IB Barsoum CA Smallwood DR Siemens CH Graham A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res 2014 74 665 74 DOI: 10.1158/0008-5472.CAN-13-0992
MZ Noman G Desantis B Janji M Hasmim S Karray P Dessen V Bronte S Chouaib PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 2014 211 781 90 DOI: 10.1084/jem.20131916
EM Palsson-McDermott L Dyck Z Zasłona D Menon AF McGettrick KHG Mills LA O'Neill Pyruvate kinase M2 is required for the expression of the immune checkpoint PD-L1 in immune cells and tumors. Front Immunol 2017 8 1300 DOI: 10.3389/fimmu.2017.01300
GM Siegers I Dutta R Lai L-M Postovit Functional Plasticity of Gamma Delta T Cells and Breast Tumor Targets in Hypoxia. Front. Immunol. 2018 9 1367 DOI: 10.3389/fimmu.2018.01367
L Li B Cao X Liang S Lu H Luo Z Wang S Wang J Jiang J Lang G Zhu Microenvironmental oxygen pressure orchestrates an anti- and pro-tumoral γδ T cell equilibrium via tumor-derived exosomes. Oncogene. 2019 38 15 2830 2843 DOI: 10.1038/s41388-018-0627-z
A Chillemi V Quarona L Antonioli D Ferrari AL Horenstein F Malavasi Roles and Modalities of Ectonucleotidases in Remodeling the Multiple Myeloma Niche. Front Immunol. 2017 8 305 DOI: 10.3389/fimmu.2017.00305
AL Horenstein V Quarona D Toscani F Costa A Chillemi V Pistoia N Giuliani F Malavasi Adenosine Generated in the Bone Marrow Niche Through a CD38-Mediated Pathway Correlates with Progression of Human Myeloma. Mol Med. 2016 22 694 704 DOI: 10.2119/molmed.2016.00198
A Ohta A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironment. Front Immunol. 2016 29 7 109 DOI: 10.3389/fimmu.2016.00109
D Liang Zuo Aijun Shao Hui C Mingjiazi Kaplan Henry J. Sun Deming Roles of the Adenosine Receptor and CD73 in the Regulatory Effect of γδ T Cells. PLoS One. 2014 9 9 e108932 DOI: 10.1371/journal.pone.0108932
D Liang H Shao WK Born RL O'Brien HJ Kaplan D Sun High level expression of A2ARs is required for the enhancing function, but not for the inhibiting function, of γδ T cells in the autoimmune responses of EAU. PLoS One. 21; 2018 13 6 e0199601 DOI: 10.1371/journal.pone.0199601
JL Adams J Smothers R Srinivasan A Hoos Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov. 2015 14 9 603 222 DOI: 10.1038/nrd4596
PC Ho T Kaech SM. Reenergizing cell anti-tumor immunity by harnessing immunometabolic checkpoints and machineries. Curr Opin Immunol. 2017 46 38 44 DOI: 10.1016/j.coi.2017.04.003
UE Martinez-Outschoorn M Peiris-Pagés RG Pestell F Sotgia MP Lisanti Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol 2017 14 2 113 DOI: 10.1038/nrclinonc.2017.1
T Cascone JA McKenzie RM Mbofung S Punt Z Wang C Xu LJ Williams Z Wang CA Bristow A Carugo MD Peoples L Li T Karpinets L Huang S Malu C Creasy SE Leahey J Chen Y Chen H Pelicano C Bernatchez YNV Gopal TP Heffernan J Hu J Wang RN Amaria LA Garraway P Huang P Yang II Wistuba SE Woodman J Roszik RE Davis MA Davies JV Heymach P Hwu W Peng Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy. Cell Metab. 2018 27 5 977 987 DOI: 10.1016/j.cmet.2018.02.024
SK McBrayer JC Cheng S Singhal NL Krett ST Rosen M Shanmugam Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy. Blood 2012 119 4686 97 DOI: 10.1182/blood-2011-09-377846
S Dalva-Aydemir R Bajpai M Martinez KUA Adekola I Kandela C Wei S Singhal JE Koblinski NS Raje ST Rosen M Shanmugam Targeting the metabolic plasticity of multiple myeloma with FDAapproved ritonavir and metformin. Clin Cancer Res 2015 21 1161 71 DOI: 10.1158/1078-0432.CCR-14-1088
WY Sanchez SL McGee T Connor B Mottram A Wilkinson JP Whitehead S Vuckovic L Catley Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib. Br J Cancer. 2013 108 8 1624 33 DOI: 10.1038/bjc.2013.120
KA Zub MM Sousa A Sarno A Sharma A Demirovic S Rao C Young PA Aas I Ericsson A Sundan ON Jensen G Slupphaug Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells. PLoS One. 2015 10 3 e0119857 DOI: 10.1371/journal.pone.0119857
EM Palsson-McDermott L Dyck Z Zasłona D Menon AF McGettrick KHG Mills LA O'Neill Pyruvate Kinase M2 Is Required for the Expression of the Immune Checkpoint PD-L1 in Immune Cells and Tumors. Front Immunol. 2017 8 1300 DOI: 10.3389/fimmu.2017.01300
S Lim JB Phillips L Madeira da Silva M Zhou O Fodstad LB Owen M Tan Interplay between Immune Checkpoint Proteins and Cellular Metabolism. Cancer Res. 2017 77 6 1245 1249 DOI: 10.1158/0008-5472.CAN-16-1647
S Kleffel C Posch SR Barthel C Mueller H3 Schlapbach E Guenova CP Elco N Lee VR Juneja Q Zhan CG Lian R Thomi W Hoetzenecker A Cozzio R Dummer Jr Mihm MC KT Flaherty MH Frank GF Murphy AH Sharpe TS Kupper T Schatton Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. Cell. 2015 62 6 1242 56 DOI: 10.1016/j.cell.2015.08.052
L Janker RL Mayer A Bileck D Kreutz JC Mader K Utpatel D Heudobler H Agis C Gerner A Slany Metabolic, anti-apoptotic and immune evasion strategies of primary human myeloma cells indicate adaptations to hypoxia. Mol Cell Proteomics. 2019 18 5 936 953 DOI: 10.1074/mcp.RA119.001390
J Neuzil LF Dong J Rohlena J Truksa SJ Ralph Classification of mitocans, anti-cancer drugs acting on mitochondria. Mitochondrion. 2013 13 3 199 208 DOI: 10.1016/j.mito.2012.07.112
E Bergaggio C Riganti G Garaffo N Vitale E Mereu C Bandini E Pellegrino V Pullano P Omedè K Todoerti L Cascione V Audrito A Riccio A Rossi F Bertoni S Deaglio A Neri A Palumbo R Piva IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies. Blood. 2018 133 2 156 167 DOI: 10.1182/blood-2018-05-850826
NE Scharping AV Menk RS Moreci RD Whetstone RE Dadey SC Watkins RL Ferris GM Delgoffe The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction. Immunity. 2016 45 3 701 703 DOI: 10.1016/j.immuni.2016.08.009
OU Kawalekar RS O'Connor JA Fraietta L Guo SE McGettigan Jr Posey AD PR Patel S Guedan J Scholler B Keith NW Snyder IA Blair MC Milone CH June Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. Immunity. 2016 44 2 380 90 DOI: 10.1016/j.immuni.2016.01.021
JAC Van Bruggen Martens Anne W. J. Fraietta Joseph A Hofland Tom Tonino Sanne Eldering Eric Levin Mark-David Siska Peter J. Endstra Sanne Rathmell Jeffrey C June Carl H Porter David L. Melenhorst J. Joseph Windt Gerritje J. W. van der P Arnon Kater. Chronic Lymphocytic Leukemia Cells Impair Mitochondrial Fitness in CD8+ T Cells and Impede CAR T Cell Efficacy. Blood 132:235 (2018) DOI: 10.1182/blood.2018885863
Wigerup C Pahlman S Bexell D Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer Pharmacology & Therapeutics 2016 164 152 169 DOI: 10.1016/j.pharmthera.2016.04.009
G Noël M Langouo Fontsa K Willard-Gallo The impact of tumor cell metabolism on T cell-mediated immune responses and immuno-metabolic biomarkers in cancer. Semin Cancer Biol. 52(Pt 2): 2018 66 74 DOI: 10.1016/j.semcancer.2018.03.003
L Li B Cao X Liang S Lu H Luo Z Wang S Wang J Jiang J Lang G Zhu Microenvironmental oxygen pressure orchestrates an anti- and pro-tumoral γδ T cell equilibrium via tumor-derived exosomes. Oncogene. 2019 38 15 2830 2843 DOI: 10.1038/s41388-018-0627-z
DJ Manalo A Rowan T Lavoie L Natarajan BD Kelly SQ Ye JG Garcia GL Semenza Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood. 2005 105 2 659 69 DOI: 10.1182/blood-2004-07-2958
P Ugocsai A Hohenstatt G Paragh G Liebisch T Langmann Z Wolf T Weiss P Groitl T Dobner P Kasprzak L Göbölös A Falkert B Seelbach-Goebel A Gellhaus E Winterhager M Schmidt GL Semenza G Schmitz HIF-1beta determines ABCA1 expression under hypoxia in human macrophages. Int J Biochem Cell Biol. 2010 42 2 241 52 DOI: 10.1016/j.biocel.2009.10.002
SM Hatfield J Kjaergaard D Lukashev TH Schreiber B Belikoff R Abbott S Sethumadhavan P Philbrook K Ko R Cannici M Thayer S Rodig JL Kutok EK Jackson B Karger ER Podack A Ohta MV Sitkovsky Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci Transl Med. 2015 7 277 277ra30 DOI: 10.1126/scitranslmed.aaa1260
NE Scharping AV Menk RD Whetstone X Zeng GM Delgoffe Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia. Cancer Immunol Res. 2017 5 1 9 16 DOI: 10.1158/2326-6066.CIR-16-0103
AK Mishra D Dingli Metformin inhibits IL-6 signaling by decreasing IL-6R expression on multiple myeloma cells. Leukemia. 2019 Apr 15. DOI: 10.1038/s41375-019-0470-4
D Wakita K Sumida Y Iwakura H Nishikawa T Ohkuri K Chamoto H Kitamura T Nishimura Tumor-infiltrating IL-17-producing gammadelta T cells support the progression of tumor by promoting angiogenesis. Eur J Immunol. 2010 40 7 1927 37 DOI: 10.1002/eji.200940157
P Icard S Shulman D Farhat JM Steyaert M Alifano H Lincet How the Warburg effect supports aggressiveness and drug resistance of cancer cells? Drug Resist Updat. 2018 38 1 11 DOI: 10.1016/j.drup.2018.03.001
JP Laubach CJ Liu NS Raje AJ Yee P Armand RL Schlossman J Rosenblatt J Hedlund M Martin C Reynolds KH Shain I Zackon L Stampleman P Henrick B Rivotto KTV Hornburg HJ Dumke S Chuma A Savell DR Handisides S Kroll KC Anderson PG Richardson IM Ghobrial A Phase I/II Study of Evofosfamide, A Hypoxia-activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma. Clin Cancer Res. 2019 25 2 478 48 DOI: 10.1158/1078-0432.CCR-18-1325
W Yang Y Bai Y Xiong J Zhang S Chen X Zheng X Meng L Li J Wang C Xu C Yan L Wang CC Chang TY Chang T Zhang P Zhou BL Song W Liu SC Sun X Liu BL Li C Xu Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. Nature. 2016 531 7596 651 5 DOI: 10.1038/nature17412
Y Kidani SJ Bensinger Modulating Cholesterol Homeostasis to Build a Better T Cell. Cell Metab. 4; 2009 23 6 963 964 DOI: 10.1016/j.cmet.2016.05.015
T Minegaki Pharmacy Journal of T Pharmacology 2018). Minegaki S Koiki Y Douke C Yamane A Suzuki M Mori M Tsujimoto K Nishiguchi Augmentation of the cytotoxic effects of nitrogen-containing bisphosphonates in hypoxia. J Pharm Pharmacol. 2018 70 8 1040 1047 DOI: 10.1111/jphp.12934
M Fiorillo M Peiris-Pagès R Sanchez-Alvarez L Bartella L Di Donna V Dolce G Sindona F Sotgia AR Cappello MP Lisanti Bergamot natural products eradicate cancer stem cells (CSCs) by targeting mevalonate, Rho-GDI-signalling and mitochondrial metabolism. Biochim Biophys Acta Bioenerg. 2018 1859 9 984 996 DOI: 10.1016/j.bbabio.2018.03.018
WW Wong JW Clendening A Martirosyan PC Boutros C Bros F Khosravi I Jurisica AK Stewart PL Bergsagel LZ Penn Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma. Mol Cancer Ther. 2007 6 6 1886 97 DOI: 10.1158/1535-7163.MCT-06-0745
JW Clendening A Pandyra Z Li PC Boutros A Martirosyan R Lehner I Jurisica S Trudel LZ Penn Exploiting the mevalonate pathway to distinguish statin-sensitive multiple myeloma. Blood. 2010 115 23 4787 97 DOI: 10.1182/blood-2009-07-230508
CA Goard M Chan-Seng-Yue PJ Mullen AD Quiroga AR Wasylishen JW Clendening DH Sendorek S Haider R Lehner PC Boutros LZ Penn Identifying molecular features that distinguish fluvastatin-sensitive breast tumor cells. Breast Cancer Res Treat. 2014 143 2 301 12 DOI: 10.1007/s10549-013-2800-y
F1 Fiore B Castella B Nuschak R Bertieri S Mariani B Bruno F Pantaleoni M Foglietta M Boccadoro M Massaia Enhanced ability of dendritic cells to stimulate innate and adaptive immunity on short-term incubation with zoledronic acid. Blood. 2007 110 3 921 7 DOI: 10.1182/blood-2006-09-044321
D Howie A Ten Bokum AS Necula SP Cobbold H Waldmann The Role of Lipid Metabolism in T Lymphocyte Differentiation and Survival. Front Immunol. 2017 8 1949 DOI: 10.3389/fimmu.2017.01949
Berod L. Friedrich C. Nandan A. Freitag J. Hagemann S. Harmrolfs K. Sandouk A. Hesse C. Castro C.N. Bähre H. Tschirner S.K. Gorinski N. Gohmert M. Mayer C.T. Huehn J. Ponimaskin E. Abraham W.R. Müller R. Lochner M. Sparwasser T De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 2014 20 11 1327 33 DOI: 10.1038/nm.3704
Buck M.D. O'Sullivan D. Geltink R.I. Klein Curtis J.D. Chang C.H. Sanin D.E. Qiu J. Kretz O. Braas D. Windt G.J. van der Chen Q. Huang S.C. O'Neill C. Edelson B.T. Pearce E.J. Sesaki H. Huber T.B. Rambold A.S. Pearce E.L. Mitochondrial dynamics controls T Cell fate through metabolic programming. Cell 166 (1) 2016 63 76 DOI: 10.1016/j.cell.2016.05.035
GJ van der Windt B Everts CH Chang JD Curtis TC Freitas E Amiel EJ Pearce EL Pearce Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012 36 68 78 DOI: 10.1016/j.immuni.2011.12.007
Y Zhang R Kurupati L Liu XY Zhou G Zhang A Hudaihed F Filisio W Giles-Davis X Xu GC Karakousis LM Schuchter W Xu R Amaravadi M Xiao N Sadek C Krepler M Herlyn GJ Freeman JD Rabinowitz HCJ Ertl Enhancing CD8(+) T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy. Cancer Cell. 2017 32 3 377 391 DOI: 10.1016/j.ccell.2017.08.004
K Chamoto PS Chowdhury A Kumar K Sonomura F Matsuda S Fagarasan T Honjo Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proc Natl Acad Sci U S A. 2017 114 5 E761 E770 DOI: 10.1073/pnas.1620433114
A Angelin L Gil-de-Gómez S Dahiya J Jiao L Guo MH Levine Z Wang WJ Quinn PK Kopinski L Wang T Akimova Y Liu TR Bhatti R Han BL Laskin JA Baur IA Blair DC Wallace WW Hancock UH Beier Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell. Metab. 2017 25 282 1293 DOI: 10.1016/j.cmet.2016.12.018
Hossain F. Al-Khami A.A. Wyczechowska D. Hernandez C. Zheng L. Reiss K. Valle L.D. Trillo-Tinoco J. Maj T. Zou W. Rodriguez P.C. Ochoa A.C Inhibition of fatty acid oxidation modulates immunosuppressive functions of Myeloid-derived suppressor cells and enhances cancer therapies. Cancer Immunol. Res. 2015 3 11 1236 47 DOI: 10.1158/2326-6066.CIR-15-0036
Kumar V. Patel S. Tcyganov E. Gabrilovich D.I. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 2016 37 3 208 220 DOI: 10.1016/
M Masarwi A DeSchiffart J Ham MR Reagan Multiple Myeloma and Fatty Acid Metabolism. JBMR Plus. 2019 3 3 e10173 DOI: 10.1002/jbm4.10173
J Storch AE Thumser The fatty acid transport function of fatty acidbinding proteins. Biochim Biophys Acta_Mol Cell Biol Lipids. 2000 1486 1 28 44 DOI: 10.1016/S1388-1981(00)00046-9
A Stahl RE Gimeno LA Tartaglia HF Lodish Fatty acid transport proteins: a current view of a growing family. Trends Endocrinol Metab. 2001 12 6 266 73 DOI: 10.1016/S1043-2760(01)00427-1
JM Tirado-Vélez I Joumady A Sáez-Benito I Cózar-Castellano G Perdomo Inhibition of fatty acid metabolism reduces human myeloma cells proliferation. PLoS One. 2012 7 9 e46484 DOI: 10.1371/journal.pone.0046484
R Loschinski M Böttcher A Stoll H Bruns A Mackensen D Mougiakakos IL-21 modulates memory and exhaustion phenotype of T-cells in a fatty acid oxidation-dependent manner. Oncotarget. 2018 9 17 13125 13138 DOI: 10.18632/oncotarget.24442
A Thedrez C Harly A Morice S Salot M Bonneville E Scotet IL-21-mediated potentiation of antitumor cytolytic and proinflammatory responses of human Vgamma 9V delta 2 T cells for adoptive immunotherapy. J Immunol. 2009 182 6 3423 31 DOI: 10.4049/jimmunol.0803068
K Wu H Zhao Y Xiu Z Li J Zhao S Xie H Zeng H Zhang L Yu B Xu IL-21-mediated expansion of Vγ9Vδ2 T cells is limited by the Tim-3 pathway. Int Immunopharmacol. 2019 69 136 142 DOI: 10.1016/j.intimp.2019.01.027
Y Zhao C Niu J Cui Gamma-delta (γδ) T cells: friend or foe in cancer development? J Transl Med. 2018 16 1 3 DOI: 10.1186/s12967-018-1491-x
AJ Muller JB DuHadaway PS Donover E Sutanto-Ward GC Prendergast Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med. 2005 11 3 312 9 DOI: 10.1038/nm1196
X Liu N Shin HK Koblish G Yang Q Wang K Wang L Leffet MJ Hansbury B Thomas M Rupar P Waeltz KJ Bowman P Polam RB Sparks EW Yue Y Li R Wynn JS Fridman TC Burn AP Combs RC Newton PA Scherle Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood. 2010 115 17 3520 30 DOI: 10.1182/blood-2009-09-246124
X Li M Wenes P Romero SC Huang SM Fendt PC Ho Navigating metabolic pathways to enhance antitumour immunity and immunotherapy. Nat Rev Clin Oncol. 2019 Mar 26.
RB Holmgaard D Zamarin DH Munn JD Wolchok JP Allison Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med. 2013 210 7 1389 402 DOI: 10.1084/jem.20130066
G An C Acharya X Feng K Wen M Zhong L Zhang NC Munshi L Qiu YT Tai KC Anderson Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication. Blood. 2016 128 12 1590 603 DOI: 10.1182/blood-2016-03-707547
Speiser D. E. Ho P. C. Verdeil G Regulatory circuits of T cell function in cancer. Nat. Rev. Immunol. 2016 16 599 611 DOI: 10.1038/nri.2016.80
He X. Lin H. Yuan L. Li B Combination therapy with L- arginine and alpha- PD-L1 antibody boosts immune response against osteosarcoma in immunocompetent mice. Cancer Biol. Ther. 2017 18 94 100 DOI: 10.1080/15384047.2016.1276136
SM Steggerda MK Bennett J Chen E Emberley T Huang JR Janes W Li AL MacKinnon A Makkouk G Marguier PJ Murray S Neou A Pan F Parlati MLM Rodriguez LA Van de Velde T Wang M Works J Zhang W Zhang MI Gross Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment. J Immunother Cancer. 2017 5 1 101 DOI: 10.1186/s40425-017-0308-4
Arginase inhibitor INCB001158 as a single agent and in combination with immune checkpoint therapy in patients with advanced/metastatic solid tumors. ClinicalTrials gov (2017). Available from:
F Qiu J Huang M Sui Targeting arginine metabolism pathway to treat arginine-dependent cancers. Cancer Lett. 2015 364 1 7 DOI: 10.1016/j.canlet.2015.04.020
MM Phillips MT Sheaff PW Szlosarek Targeting arginine-dependent cancers with arginine-degrading enzymes: opportunities and challenges. Cancer Res Treat. 2013 45 251 62 DOI: 10.4143/crt.2013.45.4.251
F Qiu YR Chen X Liu CY Chu LJ Shen J Xu S Gaur HJ Forman H Zhang S Zheng Y Yen J Huang HJ Kung DK Ann Arginine starvation impairs mitochondrial respiratory function in ASS1-deficient breast cancer cells Sci. Signal. 2014 7ra31 DOI: 10.1126/scisignal.2004761
MP Kelly AA Jungbluth BW Wu J Bomalaski LJ Old G Ritter Arginine deiminase PEG20 inhibits growth of small cell lung cancers lacking expression of argininosuccinate synthetase Br. J. Cancer 106 2011 324 332 DOI: 10.1038/bjc.2011.524
HJ Tsai SS Jiang WC Hung G Borthakur SF Lin N Pemmaraju E Jabbour JS Bomalaski YP Chen HH Hsiao MC Wang CY Kuo H Chang SP Yeh J Cortes LT Chen TY Chen A phase II study of arginine deiminase (ADI- PEG20) in relapsed/refractory or poor- risk acute myeloid leukemia patients. Sci. Rep. 2017 7 1 11253 DOI: 10.1038/s41598-017-10542-4
V Bansal P Rodriguez G Wu DC Eichler J Zabaleta F Taheri JB Ochoa Citrulline can preserve proliferation and prevent the loss of CD3 zeta chain under conditions of low arginine. J Parenter Enteral Nutr. 2004; 28 423 430 DOI: 10.1177/0148607104028006423
M Fletcher ME Ramirez RA Sierra P Raber P Thevenot AA Al-Khami D Sanchez-Pino C Hernandez DD Wyczechowska AC Ochoa PC Rodriguez L-Arginine depletion blunts anti-tumor T cell responses by inducing myeloid-derived suppressor cells. Cancer Res. 2015 75 275 83 DOI: 10.1158/0008-5472.CAN-14-1491
PC Rodriguez DG Quiceno AC Ochoa L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood. 2007 109 1568 73 DOI: 10.1182/blood-2006-06-031856
E Brin K Wu HT Lu Y He Z Dai W He PEGylated arginine deiminase can modulate tumor immune microenvironment by affecting immune checkpoint expression, decreasing regulatory T cell accumulation and inducing tumor T cell infiltration. Oncotarget 2017 8 35 58948 58963 DOI: 10.18632/oncotarget.19564
A Romano NL Parrinello P La Cava D Tibullo C Giallongo G Camiolo F Puglisi M Parisi MC Pirosa E Martino C Conticello GA Palumbo F Di Raimondo PMN-MDSC and arginase are increased in myeloma and may contribute to resistance to therapy. Expert Rev Mol Diagn. 2018 18 7 675 683 DOI: 10.1080/14737159.2018.1470929
P Serafini K Meckel M Kelso K Noonan J Califano W Koch L Dolcetti V Bronte I Borrello Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med. 2006 203 12 2691 702 DOI: 10.1084/jem.20061104
KA Noonan N Ghosh L Rudraraju M Bui I Borrello Targeting immune suppression with PDE5 inhibition in end-stage multiple myeloma. Cancer Immunol Res. 2014 2 8 725 31 DOI: 10.1158/2326-6066.CIR-13-0213
P Serafini Myeloid derived suppressor cells in physiological and pathological conditions: the good, the bad, and the ugly. Immunol. Res. 2013 57 172 184 DOI: 10.1007/s12026-013-8455-2
C De Santo P Serafini I Marigo L Dolcetti M Bolla P Del Soldato C Melani C Guiducci MP Colombo M Iezzi P Musiani P Zanovello V Bronte Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proc. Natl Acad. Sci. USA 2005 102 4185 4190 DOI: 10.1073/pnas.0409783102
L Douguet L Bod R Lengagne L Labarthe M Kato MF Avril A Prévost-Blondel Nitric oxide synthase 2 is involved in the pro-tumorigenic potential of γδ17 T cells in melanoma. Oncoimmunology. 2016 5 8 e1208878 DOI: 10.1080/2162402X.2016.1208878
BJ Altman ZE Stine CV Dang From krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer 2016 16 10 619 34 DOI: 10.1038/nrc.2016.71
F Parlati M Gross J Janes E Lewis A MacKinnon M Rodriguez P Shwonek M Bennett Glutaminase inhibitor CB-839 synergizes with pomalidomide in preclinical multiple myeloma models (abstract). Blood. 14; 2014 124 21
DT Vogl A Younes K Stewart K William Orford M Bennett D Siegel JG Berdeja Phase 1 study of CB-839, a first-in-class, glutaminase inhibitor in patients with multiple myeloma and lymphoma. Blood. 2015 126 23 3059 3059
R Bajpai SM Matulis C Wei AK Nooka HE Von Hollen S Lonial LH Boise M Shanmugam Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 eliciting synthetic lethality to venetoclax. Oncogene. 2016 35 30 3955 64 DOI: 10.1038/onc.2015.464
MO Johnson MM Wolf MZ Madden G Andrejeva A Sugiura DC Contreras D Maseda MV Liberti K Paz RJ Kishton ME Johnson AA de Cubas P Wu G Li Y Zhang DC Newcomb AD Wells NP Restifo WK Rathmell JW Locasale ML Davila BR Blazar JC Rathmell Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism. Cell. 2018 175 7 1780 1795 DOI: 10.1016/j.cell.2018.10.001
D Wakita K Sumida Y Iwakura H Nishikawa T Ohkuri K Chamoto H Kitamura T Nishimura Tumor-infiltrating IL-17-producing gammadelta T cells support the progression of tumor by promoting angiogenesis. Eur J Immunol. 2010 40 7 1927 37 DOI: 10.1002/eji.200940157
AL Horenstein V Quarona D Toscani F Costa A Chillemi V Pistoia N Giuliani F Malavasi Adenosine generated in the bone marrow niche through a CD38-mediated pathway correlates with progression of human myeloma. Mol. Med. 2016 22 694 704 DOI: 10.2119/molmed.2016.00198
Allard B. Pommey S. Smyth M.J. Stagg J Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin Cancer Res. 2013 19 5626 5635 DOI: 10.1158/1078-0432.CCR-13-0545
PA Beavis N Milenkovski MA Henderson LB John B Allard S Loi MH Kershaw J Stagg PK Darcy Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses. Cancer Immunol.Res. 2015 3 506 517 DOI: 10.1158/2326-6066.CIR-14-0211
D Mittal A Young K Stannard M Yong MW Teng B Allard J Stagg MJ Smyth Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res. 2014 74 3652 8 DOI: 10.1158/0008-5472.CAN-14-0957
A Chillemi V Quarona L Antonioli D Ferrari AL Horenstein F Malavasi Roles and Modalities of ectonucleotidases in Remodeling the Multiple Myeloma Niche. Front Immunol. 2017 8 305 DOI: 10.3389/fimmu.2017.00305
Yang Rui Elsaadi Samah Misund Kristine Slupphaug Geir Menu Eline Hay Carl Cooper Zac Vanderkerken Karin Børset Magne CD39 Anne Marit Sponaas. Role of ectoenzymes Suppl) CD73 in the immune response to multiple myeloma (abstract). Cancer Res 78(13 Abstract nr LB-117 (2018) DOI: 10.1158/1538-7445.AM2018-LB-117
RJ Rickles LT Pierce 3rd Giordano TP WF Tam DW McMillin J Delmore JP Laubach AA Borisy PG Richardson MS Lee Adenosine A2A receptor agonists and PDE inhibitors: a synergistic multitarget mechanism discovered through systematic combination screening in B-cell malignancies. Blood. 2010 116 4 593 602 DOI: 10.1182/blood-2009-11-252668
AL Horenstein A Chillemi G Zaccarello S Bruzzone V Quarona A Zito S Serra F Malavasi A CD38/CD203a/CD73 ectoenzymatic pathway independent of CD39 drives a novel adenosinergic loop in human T lymphocytes Oncoimmunology 2013 2 e26246 DOI: 10.4161/onci.26246
F Morandi AL Horenstein F Costa N Giuliani V Pistoia F Malavasi CD38: A Target for Immunotherapeutic Approaches in Multiple Myeloma. Front Immunol. 2018 9 2722 DOI: 10.3389/fimmu.2018.02722
NWCJ van de Donk PG Richardson F Malavasi CD38 antibodies in multiple myeloma: back to the future. Blood. 2018 131 1 13 29
L Chen L Diao Y Yang X Yi BL Rodriguez Y Li PA Villalobos T Cascone X Liu L Tan PL Lorenzi A Huang Q Zhao D Peng JJ Fradette DH Peng C Ungewiss J Roybal P Tong J Oba F Skoulidis W Peng BW Carter CM Gay Y Fan CA Class J Zhu J Rodriguez-Canales M Kawakami LA Byers SE Woodman VA Papadimitrakopoulou E Dmitrovsky J Wang SE Ullrich II Wistuba JV Heymach FX Qin DL Gibbons CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1/PD-L1 blockade. Cancer Discov. 2018 8 9 1156 1175 DOI: 10.1158/2159-8290.CD-17-1033
D Liang A Zuo H Shao M Chen HJ Kaplan D Sun Roles of the adenosine receptor and CD73 in the regulatory effect of γδ T cells. PLoS One. 2014 9 9 e108932 DOI: 10.1371/journal.pone.0108932
D Liang A Zuo R Zhao H Shao WK Born RL O'Brien HJ Kaplan D Sun CD73 Expressed on γδ T Cells Shapes Their Regulatory Effect in Experimental Autoimmune Uveitis. PLoS One. 2016 11 2 e0150078 DOI: 10.1371/journal.pone.0150078
D Liang H Shao WK Born RL O'Brien HJ Kaplan D Sun High level expression of A2ARs is required for the enhancing function, but not for the inhibiting function, of γδ T cells in the autoimmune responses of EAU. PLoS One. 2018 13 6 e0199601 DOI: 10.1371/journal.pone.0199601
MW Traxlmayr D Wesch AM Dohnal P Funovics MB Fischer D Kabelitz T Felzmann Immune suppression by gammadelta T-cells as a potential regulatory mechanism after cancer vaccination with IL-12 secreting dendritic cells. J Immunother 2010 33 1 40 52 DOI: 10.1097/CJI.0b013e3181b51447
C Barjon HA Michaud A Fages C Dejou A Zampieri L They A Gennetier F Sanchez L Gros JF Eliaou N Bonnefoy V Lafont IL-21 promotes the development of a CD73-positive Vγ9Vδ2 T cell regulatory population. Oncoimmunology. 2017 7 1 e1379642 DOI: 10.1080/2162402X.2017.1379642
G Gruenbacher H Gander A Rahm M Idzko O Nussbaumer M Thurnher Ecto-ATPase CD39 Inactivates Isoprenoid-Derived Vγ9Vδ2 T Cell Phosphoantigens. Cell Rep. 2016 16 444 456 DOI: 10.1016/j.celrep.2016.06.009
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