IMR Press / FBL / Volume 24 / Issue 7 / DOI: 10.2741/4779
Open Access Review
Macrophages at the crossroads of anticancer strategies
Show Less
1 Department of Immunology and Inflammation, Humanitas Clinical and Research Center-IRCCS, Rozzano, Milan, Italy
2 Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
3 Department of Biomedical Science, Humanitas University, Rozzano, Italy
4 Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy
*Correspondence: (Federica Marchesi)
Front. Biosci. (Landmark Ed) 2019, 24(7), 1271–1283;
Published: 1 June 2019
(This article belongs to the Special Issue Targeting of immune system in anti-tumor combined therapies)

Macrophages are essential elements in the tumor microenvironment, where they can promote tumor growth but also influence the efficacy of anticancer strategies. In conventional therapies, chemotherapy and radiotherapy, TAMs play a dichotomous role, contributing to antitumor activity or hindering the efficacy of cytoreductive therapies. Macrophages express checkpoint ligands and are therefore targets of immunotherapy approaches based on checkpoint inhibitors. Targeted therapies with monoclonal antibodies elicit TAMs to engage in antitumor functions such as antibody-dependent phagocytosis through the activation of Fc receptors. New approaches to exploit macrophage effector functions induced by therapeutic antibodies are under investigation. Finally, strategies aimed at targeting TAM recruitment, survival and functional polarization are advancing towards the clinic. Collectively, TAM-centered strategies will hopefully complement conventional and unconventional anticancer therapies to achieve improved therapeutic benefit.

Anticancer Strategies

The most frequently found cells within the tumor microenvironment are tumor-associated macrophages (TAMs) (1, 2). Due to their distinctive plasticity, macrophages are able to profoundly reprogram their functions in response to a wide variety of signals, both in physiological and pathological conditions. The combination of these signals determines the differentiation and the activation status of these cells.

The ability of macrophages to respond to different environmental cues resulting in the acquisition of distinct functional phenotypes has brought about a conventional/widely-accepted classification, referred to as M1/M2 dichotomy (3). Early studies indicated two main functional states: an activated phenotype (M1) and an alternatively activated phenotype (M2) (4). The classical M1 activation is induced by recognition of pathogen-associated moieties, such as lipopolysaccharides (LPS), via TLR ligands, and Th1 cytokines, such as Interferon gamma (INFγ), and is characterized by high levels of proinflammatory cytokines (IL1β, TNFα, IL-6, IL-23) and chemokines (CXCL9, CXCL10), increased production of reactive oxygen/nitrogen intermediates (ROI/RNI), promotion of Th1 type immune responses, and strong microbicidal and tumoricidal activity (3). Conversely, M2 macrophages respond to Th2 cytokines, IL-4 and IL-13, and are characterized by avid phagocytic activity and increased expression of scavenger receptors including CD163, mannose receptor (MR), and galactose receptor (GR), production of ornithine and polyamines via the arginase pathway, and reduced expression of inflammatory cytokines. Alternatively activated macrophages have an immunoregulatory role, and are involved in the containment of parasite (helminth) infections, tissue remodeling and tumor promotion.

While this classification might be suitable for extreme activation states such as M1 in Th1 type responses or M2 in parasite infections, and despite the fact that M1 and M2 macrophages have been detected in several pathological contexts such as sepsis, obesity, and tumors, the scenario in vivo is likely to be much more complex (4). Recently, it has been suggested that macrophages exposed to excessive stimuli, both M1 or M2, undergo a “switching” phenotype resulting in the counteractive production of mediators capable to dampen the initial stimulus (5, 6). According to this scenario, they would respond to persistent proinflammatory stimuli by reprogramming towards M2 and vice versa, integrating the type of stimulus and the phenotypic response through various intracellular signaling pathways including the JNK, PI3K/Akt, Notch, JAK/STAT, TGF-β/SMAD/non-SMAD, TLR/NF-κB (5).

In general, considering the plasticity of these cells and the complex in vivo milieu of cytokines and stimuli, often macrophages in vivo present with a mixture of these two phenotypes. It is also possible for macrophages to shift from one activation state to another during the course of an immune response or pathological context (4). Given all the above, M1 and M2 macrophages should be considered as the extremes of a single contiguous spectrum of activation states that characterize differentiated macrophages (4). Additionally, transcriptional profiling, within the “Immunological Genome Project”, of murine tissue macrophages in homeostatic conditions, found very high transcriptional diversity and minimal overlap between macrophages from different organs, strongly suggesting a highly heterogeneous and organ specific population of cells (7).

In the tumor context, studies have demonstrated that macrophages activated by bacterial products and cytokines acquire the capacity to kill tumor cells (8, 9). More frequently, though, TAMs are renowned for their promotion of tumor growth and metastasis, exerted by sustaining angiogenesis, matrix remodeling, and secreting growth factors and immunosuppressive cytokines (1012). In accordance with these tumor-promoting functions, in many human cancer types (breast, bladder, prostate, head and neck, glioma, melanoma, and non-Hodgkin lymphoma), high numbers of TAMs have been associated to poor prognosis in preclinical and clinical studies (2, 13). However, there are some cancer types (for example colorectal and gastric cancer) in which high infiltration of TAMs correlates with better prognosis (1416).

The wealth of studies addressing the function of macrophages and their prognostic role in human cancer sets the foundations to explore whether these important effectors of the immune response have a role in mediating the efficacy of anticancer strategies. Here we review the current understanding of how macrophages contribute to the efficacy of anticancer strategies, and, in particular, of their emerging role in targeted therapies.


Many studies have demonstrated that TAMs, besides playing a key role in tumorigenesis, also have the ability to modulate the efficacy of conventional anticancer therapies, such as chemotherapy and irradiation. Both positive and negative interactions have been documented, reflecting the complexity of the microenvironment and of macrophage functions.

3.1. In chemotherapy and radiotherapy

The modulation of chemotherapy efficacy by macrophages is complex (Figure 1). Various mechanisms have been proposed for macrophage-mediated enhanced chemosensitivity. A first mechanism involves a process known as “immunogenic cell death” (ICD). ICD implicates the release of “eat-me” signals (for example extracellular ATP, heat shock proteins, secreted type I interferon, extracellular nucleic acids and many others still being unearthed) from tumor cells killed by cytotoxic agents, such as Doxorubicin, Oxaliplatin, Cyclophosphamide (17). These signals activate the phagocytic and antigen presenting abilities of innate immune cells, such as macrophages and DCs, which in turn are able to promote T cell responses against tumor antigens (1822). This reinstatement of an anti-tumor immune response triggered by conventional anticancer therapies acquires particular relevance in the perspective of combinatorial strategies. Therefore, efforts are ongoing to identify anticancer agents driving bona fide immunogenic cell death to be tested in combination with immunotherapeutic strategies. Concomitantly, the attention is focused on those features of the tumor immune microenvironment that could provide an indication regarding the efficacy of the anticancer strategy, for instance the presence and density of antigen-presenting cells and their functional state.

Figure 1.

Distinct mechanisms mediating the interaction of macrophages with chemotherapy and radiotherapy. Macrophages contribute to the efficacy of conventional anticancer strategies by either synergizing or interfering with chemotherapy and radiotherapy. Clockwise: macrophages enhance sensitivity to selective chemotherapeutic agents inducing “immunogenic cell death”; some agents directly modulate macrophage polarization state, or selectively deplete TAMs; low-dose irradiation can drive macrophage functions to an antitumor mode, resulting in systemic tumor regression (abscopal effect) or directly modify macrophage activation. On the other hand, radiotherapy can negatively polarize macrophages or recruit pro-fibrotic myeloid cells. Interference of macrophages with chemotherapy entails macrophage capability to secrete factors nourishing and protecting tumor cells from chemotherapy, involvement of macrophages in the fibrotic reaction after chemotherapy induced tissue damage and recruitment of immunosuppressive myeloid population by chemotherapy.

A second mechanism is related to the potential effect of chemotherapy on macrophage phenotype. Both in pancreatic (15) and colorectal cancer (16), a high density of macrophages associated to a better prognosis only in chemotherapy-treated patients. The enhanced chemosensitivity hinged on the ability of the cytotoxic agents, gemcitabine and 5-fluorouracil, to reprogram macrophages from a protumoral phenotype to anti tumoral; such reprogramming, which was reflected in a change of transcriptional profile and surface marker expression towards M1, resulted in enhanced killing of tumor cells (15, 16).

Other mechanisms through which chemotherapy interacts with myeloid cells to the result of increased efficacy involve the depletion of immunosuppressive TAMs, as is the case of Trabectedin treatment for soft tissue sarcomas (23). This antitumor DNA-binding agent is selectively cytotoxic for TAMs and their circulating precursors (monocytes) by a mechanism involving selective activation of caspase-dependent apoptosis in cells of the monocyte lineage expressing the TRAIL-receptor. This macrophage-depleting effect has been shown to account for most of its antitumor activity (23). Another antitumor drug, Docetaxel, has been shown to have chemoimmunomodulating properties in a preclinical model of breast cancer (24). Here, Docetaxel treatment significantly reduced the expression of M2 markers (e.g. IL-10 and mannose receptor) and raised the expression of M1 markers (e.g. IL-12 and CCR7) in myeloid derived suppressor cells (including cells of the monocyte-macrophage lineage).

Negative effects of macrophages on responsiveness to chemotherapy are also well documented, mainly in preclinical models. The mechanisms outlined for TAM-mediated chemoresistance are often direct consequence of the most peculiar features of macrophages, namely orchestrating an immunosuppressive response, tissue-repair related functions and nourishment of tumor cells. In line with this, depletion of TAMs via anti-CSF1 antibodies resulted in enhanced chemosensitivity in a combinatorial chemotherapeutic approach in human breast cancer xenografts (25). Multiple mechanisms mediated the enhanced chemosensitivity induced by depletion of TAMs, including suppression of genes involved in chemoresistance of tumor cells and downregulation of metalloproteases contributing to tumor matrix remodeling. This evidence strongly shows the potent contribution of macrophages to tumor growth and how this can be detrimental in chemotherapeutic regimens. In a similar manner, macrophage depletion in a murine model of breast cancer was found to increase responsiveness to paclitaxel (PTX) treatment. The damage induced by PTX treatment, in fact, increased the recruitment of immunosuppressive myeloid cells, hampering the adaptive antitumor immune response (26). Other mechanisms of TAMs fostering chemoresistance involve the release of factors, such as Cathepsin B, that protect cancer cells from chemotherapy-related cytotoxicity (27), or the release of survival signals for cancer stem cells, such as milk fat globule-epidermal growth factor 8 protein (MFG-E8), limiting the effect of cisplatin on colon and lung cancer cells (28). Moreover, targeting the pro-angiogenic features of TAMs, decreasing the expression of vascular endothelial growth factor (VEGF) or placental growth factor (PlGF), resulted in ameliorated delivery of chemotherapeutic agents by improving vascular leakiness (29, 30). In colorectal cancer, the role of TAMs is still controversial. In a recent paper, macrophage infiltration associated with chemoresistance of colon cancer cell lines to 5-florouracil via the production of IL6 by TAMs which, acting on the IL6R/STAT3 axis in tumor cells, inhibited the tumor suppressor miR-204-5p (31).

Important and divergent interactions between macrophages and anticancer therapies have been shown also for radiotherapy regimens (32, 33), although molecular mediators of immunogenic cell death and type of myeloid cell activation can significantly vary compared to the ones induced by chemotherapy. Besides hitting tumor cells, in fact, radiation therapy profoundly affects the composition of the tumor microenvironment, inducing important modifications that can affect the overall type of immune response. Among others, the induction of transforming growth factor beta (TGFβ) by radiation therapy (34) holds a key role in the immunosuppressive polarization of macrophages. Also, the influx of tumor-infiltrating myeloid cells, including TAMs and myeloid derived suppressor cells, after radiotherapy has been shown to drive a fibrotic reaction that can promote tumor recurrence (35); administration of a selective inhibitor of CSF-1R has been shown to block this fibrotic reaction.

However, macrophages might be involved in the systemic “abscopal” effect induced by radiotherapy, a condition that is sometimes observed in patients when tumor regression occurs at sites distant from the irradiated lesions. The systemic reprogramming of the anti-tumor immune response induced by radiotherapy is more frequently ascribed to the antigen-presenting capability of dendritic cells, while macrophages have been more implicated as a hindrance to the radiation-induced immunity (36). However, reports have shown that neoadjuvant low-dose irradiation can elicit immunostimulatory macrophage functions, by programming the differentiation of NOS1+ M1 macrophages in human pancreatic adenocarcinoma (32, 33). Collectively, macrophages have the potential to both reduce and magnify the efficacy of radiotherapy depending on the context.


Macrophage capability to mediate efficacy of immunotherapeutic strategies has been relatively neglected, likely due to the biased view of these phagocytes as mediators of tumor progression. However, given the important contribution of TAMs to tumor biology in multiple tumor types, it is expected that macrophages and their potential involvement in immunotherapy will raise growing interest.

4.1. In immunotherapy

Only a few years after the introduction in the clinical practice of immunomodulatory antibodies, including checkpoint inhibitors, macrophages have been shown to affect their efficacy in multiple ways. Immunomodulatory antibodies target membrane molecules with regulatory functions, such as the immunological checkpoint receptors CTLA-4 or PD-1, exploited by tumor cells to evade recognition from the immune system. These antibodies have been largely supposed to act by blocking the negative signal that is induced when the receptor on T cells binds with the corresponding ligand expressed by antigen-presenting or tumor cells. However, further mechanistic studies have shown that the in vivo activity of immunomodulatory antibodies encompasses interactions with members of the FcgR family. Specifically, FcR-mediated depletion of T regulatory cells by macrophages is required in the antitumor therapeutic effects of checkpoint inhibitors directed against CTLA-4 and GITR (37, 38), suggesting that the tissue localization of macrophages in the tumor microenvironment can significantly contribute to this function. Additionally, the expression of checkpoint ligands (such as PD-L1, PD-L2 and B7-1 and B7- 2) (3941) on macrophages makes them a key component of the immunosuppressive pathways targeted by immune-checkpoint inhibitors, and could contribute to the efficacy of these treatments (2). A recent work has unexpectedly revealed the expression of PD-1 on tumor-associated macrophages and its negative correlation with the phagocytic activity against tumor cells, suggesting another mechanism of interaction of macrophages with checkpoint inhibitors (42). Prompted by the increasing number of studies assessing the role of macrophages in checkpoint treatments, numerous clinical trials are now testing the efficacy of therapeutic regimens combining blockade of macrophages by CSF1/CSF1-R inhibitors and of checkpoint axes (43).

Very recently, histo-pathological analysis of non-small cell lung cancer specimens from patients treated with anti-PD1 in neoadjuvant regimen has evidenced macrophages in the regression bed (the area of immune-mediated tumor clearance) and their assessment has been used to build an irPRC (immune-related pathologic response criteria) scoring system (44) which could be exploited to identify standardized assays to assess immunotherapeutic efficacy.

Macrophages have also been implicated in the mechanism of action of agonistic antibodies targeting the co-stimulatory receptor CD40, by a mechanism involving polarization towards an antitumor mode of action (45). The original studies proposing macrophages as target cells of the CD40 agonists opened a new vista on the potential exploitation of these phagocytes for therapeutic purposes. In the wealth of efforts aimed at depleting macrophages in cancer, Beatty and colleagues showed that, when properly re-educated by immunomodulating agents, CD40 agonists in this case, macrophages turned into a favorable element in the tumor microenvironment, suggesting that reprogramming strategies could be efficacious approaches to enhance other forms of immunotherapy. CD40 agonists are now being tested in combination with chemotherapy, checkpoint inhibitory antibodies, and other immune modulators (46).

4.2. In targeted therapy

The number of therapeutic antibodies targeting tumor-specific antigens currently being used in the clinical setting is growing. Their mode of action encompasses different mechanisms, including block of tumor survival signals, neutralization of tumor growth factors, complement activation and engagement of effector immune cells expressing the FcR (4749).

The strategic tissue localization and the high concentration of macrophages in the tumor microenvironment (Figure 2) of many cancer types make these phagocytes ideal mediators of the efficacy of antibody-based targeted therapies. Early studies from the 1980’s assessed and demonstrated the contribution of macrophages to the mechanism of action of monoclonal antibodies in vivo (5052); however, whether the exact mode of action was phagocytosis of tumor cells rather than cytotoxicity or a mixture of both was not very clear. As professional phagocytes, in fact, macrophages recognize and engulf harmful materials by specialized receptors, including pattern recognition receptors, scavenger receptors and receptors for the Fc (fragment crystallizable) portion of antibodies (53); therefore, they are fully equipped to perform important anti-tumor functions such as phagocytosis (54) and tumor cell lysis (49).

Figure 2.

TAMs within the tumor microenvironment. TAMs accumulate in high numbers in the tumor microenvironment, making them ideal candidates for therapeutic approaches and important effectors of targeted therapies. CD68+ and CD163+ (yellow and red respectively) macrophages, CD20+ B cells (green), CD8+ T cells (magenta) and CD34+ vessels (white) in a human section of colo-rectal liver metastasis.

From an immune cell standpoint, the therapeutic antibody serves to connect the target cell with the activating type I FcR, primarily expressed on effector natural killer cells and phagocytes. Effector cells are activated to induce antibody-dependent phagocytosis (ADP) of the opsonized target or exert cytotoxicity through the release of cytotoxic mediators and antibody-dependent cell-mediated cytotoxicity (ADCC). Examples of therapeutic antibodies for which effector macrophages expressing the FcR are involved include Rituximab, targeting the CD20 B cell-differentiation antigen expressed by lymphoma and leukemia B cells (55, 56), Trastuzumab, an antibody against the erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2) (47, 5759), Cetuximab, targeting the epidermal growth factor receptor (EGFR) (49), Daratumumab targeting CD38 in myeloma cells (60). Accordingly, functional polymorphisms in human FcgRIIIA have been identified that may affect the ADCC of natural killer cells and monocyte/macrophages and correlate with response rates in lymphoma patients treated with Rituximab (61), breast cancer patients treated with Trastuzumab (59) and metastatic colo-rectal cancer treated with Cetuximab (62).

An important confirmation of the relevant role of macrophage phagocytosis induced upon recognition of therapeutic antibodies comes from the studies on the CD47/SIRPα axis. SIRPα is a negative regulator of macrophage phagocytosis and its engagement by CD47, widely expressed by many cell types, is perceived as a “don’t eat me signal” by the phagocytes. Overexpression of CD47 by tumor cells (6366) has been implicated in resistance of tumor cells to macrophage phagocytosis and its therapeutic targeting is being evaluated in clinical settings (67). Notably, the inhibition of macrophage phagocytic activity by the CD47/SIRPα axis suggests that targeting of this axis could complement antitumor antibodies and possibly reinforce their efficacy. This hypothesis has been tested and proven effective. CD47-blocking antibodies have shown synergistic activity in combination with Rituximab (63) and non-functional engineered SIRPα variants have been used as adjuvants for antitumor antibodies including Rituximab, Cetuximab and Trastuzumab (68).


Based on all the preclinical and clinical evidence highlighting a tumor-promoting role for macrophages, in recent years, many strategies targeting TAMs have been proposed. Mainly, the approaches have been focused on impeding the recruitment of monocytes/macrophages to the tumor site (by blocking the CCL2/CCR2 or the CXCL12/CXCR4 axes), interfering with differentiation and survival (targeting the CSF-1/CSF-1R pathway), and acting on polarization.

Monocyte recruitment to tumor tissues relies on several molecules including chemokines (CCL2/CCR2 and the CXCL12/CXCR4 axes), CSF-1 and VEGF. Several preclinical models of melanoma, breast, liver, lung, and prostate cancer treated with specific antibodies anti-CCL2 have shown a reduction in tumor growth and metastasization (2). In clinic however, interfering with the CCL2/CCR2 pathway has given contradictory and rather unsatisfactory results in terms of efficacy, even if generally well tolerated (69, 70). This could be due to the robustness of the chemokine family and compensatory mechanisms involving other macrophage-recruiting chemokines. CNTO88 (carlumab), a specific, inhibitory monoclonal antibody anti-CCL2, entered a phase I clinical trial for advanced solid tumors, but only showed a transient CCL2 suppression (71). Another phase I clinical trial was conducted with carlumab in combination with different chemotherapy regimens for patients with solid tumors, but again only transient depletion of CCL2 was achieved and no increased efficacy compared to chemotherapy alone (69). However, in a phase I study for pancreatic adenocarcinoma, another selective CCR2 inhibitor (PF-04136309) showed more promising results in combination with chemotherapy. Approximately 50% of patients receiving the combined treatment showed partial tumor response (70).

In a similar manner, targeting the CSF-1/CSF-1R pathway has yielded better results in combination regimens rather than alone. CSF-1 is the main cytokine for differentiation and survival for the monocyte/macrophage lineage. With the additional advantage of the receptor (CSF-1R) being expressed exclusively on monocytes, it represents an evident candidate to target macrophages. CSF-1 is also over-expressed by many tumor types, and its expression correlates with bad prognosis in various cancer types (2).

In experimental models, the monoclonal antibody RG7155 (Emactuzumab), which targets CSF-1R, was able to reduce the influx of TAMs and skew the adaptive immune infiltrate towards CD8 lymphocytes (72). Another molecule targeting CSF-1R, PLX3397 (Plerixafor) was tested for recurrent glioblastoma and demonstrated improved efficacy only when in combination with radiotherapy (73). Furthermore, in a preclinical transgenic model of pancreatic adenocarcinoma, the CSF-1R inhibitor GW2580, enhanced chemosensitivity to gemcitabine (74).

Finally, as already mentioned in the previous paragraph, macrophage targeting to the aim of functional activation was unexpectedly observed after treatment with a CD40 agonist antibody in a small group of patients treated with gemcitabine. This was reproduced in a genetically engineered mouse model of pancreatic cancer, with the result of reduced tumor growth, due to repolarization of macrophages towards a tumoricidal phenotype. Surprisingly, the mechanism was shown to be both T-cell and gemcitabine independent (45). This promising study led to a phase I clinical trial on a small group of advanced pancreatic cancer patients, testing the CD40 agonist antibody (CP-870,893) in combination with gemcitabine, which yielded only a partial tumor response (75).

A more recent study has shown that targeting the Bruton Tyrosine Kinase (BTK) pathway in a preclinical model of pancreatic cancer can lead to reactivation of the adaptive immune response, via repolarization of TAMs towards an M1-like phenotype (76).

Taken together, the preclinical and clinical evidence convincingly indicate that targeting TAMs will bring best results when in combination with standard therapies.


Macrophages are essential elements of the immune ecosystem of tumors, often present in high numbers and characterized by a peculiar malleability, which allows them to acquire both protumor and antitumor functional states. Most studies have documented the relevance of the macrophage population as a whole; however, dissecting the heterogeneity of TAMs could provide new insights on their role in the tumor microenvironment.

TAMs are important mediators of the efficacy of anticancer strategies (Figure 3). In conventional therapies, chemotherapy and radiotherapy, macrophages have been shown to both boost and limit the therapeutic effect. These observations suggest that strategies aimed at reprogramming macrophages towards an anti-tumor phenotype could yield promising results in combination with conventional cancer therapies. However, preclinical and clinical evidence varies significantly in a context-dependent manner, occasionally highlighting contradictory roles for TAMs.

Figure 3.

TAMs are important mediators of the efficacy of anticancer strategies. Synergism between TAMs and conventional therapies, chemotherapy and radiotherapy, encompasses mechanisms such as imunogenic cell death, TAM depletion and TAM reprogramming. Interference of TAMs with therapeutic effect includes orchestration of tissue fibrosis and M2-like functions. The in vivo activity of immunomodulatory antibodies encompasses also interactions with members of the FcgR family, expressed on macrophages. Macrophages express checkpoint ligands (such as PD-L1, PD-L2), thus representing a key component of the immunosuppressive pathways targeted by immune-checkpoint inhibitors. In targeted therapies, monoclonal antibodies engage macrophage antitumor functions, such as their ability of eliminating cancer cells by antibody-dependent phagocytosis and cytotoxicity.

Recent studies have evidenced a role for TAMs in immunomodulatory and targeted anticancer therapies. Monoclonal antibodies engage macrophage antitumor functions, such as their ability of eliminating cancer cells by antibody-dependent phagocytosis and cytotoxicity. Therapeutic strategies exploiting the engagement of macrophages to unleash the full potential of the innate immune system are now approaching the clinic. Hopefully, such strategies will complement conventional therapies to reach improved therapeutic benefits.


The research leading to these results has received funding from Associazione Italiana per la ricerca sul cancro (AIRC) under IG2016-ID.18443 project – P.I. Marchesi Federica and AIRC fellowship 18011 to Nina Cortese. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Authors declare no conflict of interest. The Authors declare no competing interests.

Mantovani A , Allavena P : The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med 212 , 435 445 ( 2015) DOI: 10.1084/jem.20150295
Mantovani A , Marchesi F , Malesci A , Laghi L , Allavena P : Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol ( 2017) DOI: 10.1038/nrclinonc.2016.217
Sica A , Mantovani A : Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122 , 787 795 ( 2012) DOI: 10.1172/JCI59643
Biswas SK , Allavena P , Mantovani A : Tumor-associated macrophages: functional diversity, clinical significance, and open questions. Semin Immunopathol 35 , 585 600 ( 2013) DOI: 10.1007/s00281-013-0367-7
Malyshev I , Malyshev Y : Current Concept and Update of the Macrophage Plasticity Concept: Intracellular Mechanisms of Reprogramming and M3 Macrophage “Switch” Phenotype. Biomed Res Int 2015 , 341308 ( 2015) DOI: 10.1155/2015/341308
Curi R , de Siqueira Mendes R , de Campos Crispin LA , Norata GD , Sampaio SC , Newsholme P : A past and present overview of macrophage metabolism and functional outcomes. Clin Sci (Lond) 131 , 1329 1342 ( 2017) DOI: 10.1042/CS20170220
Gautier EL , Shay T , Miller J , Greter M , Jakubzick C , Ivanov S , Helft J , Chow A , Elpek KG , Gordonov S : Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nature immunology 13 , 1118 ( 2012) DOI: 10.1038/ni.2419
Evans R , Alexander P : Cooperation of immune lymphoid cells with macrophages in tumour immunity. Nature 228 , 620 622 ( 1970) DOI: 10.1038/228620a0
Mantovani A , Bottazzi B , Colotta F , Sozzani S , Ruco L : The origin and function of tumor-associated macrophages. Immunol Today 13 , 265 270 ( 1992) DOI: 10.1016/0167-5699(92)90008-U
Mantovani A , Sica A , Locati M : Macrophage polarization comes of age. Immunity 23 , 344 346 ( 2005) DOI: 10.1016/j.immuni.2005.10.001
Wynn TA , Chawla A , Pollard JW : Macrophage biology in development, homeostasis and disease. Nature 496 , 445 455 ( 2013) DOI: 10.1038/nature12034
Murray PJ , Allen JE , Biswas SK , Fisher EA , Gilroy DW , Goerdt S , Gordon S , Hamilton JA , Ivashkiv LB , Lawrence T , Locati M , Mantovani A , Martinez FO , Mege JL , Mosser DM , Natoli G , Saeij JP , Schultze JL , Shirey KA , Sica A , Suttles J , Udalova I , van Ginderachter JA , Vogel SN , Wynn TA : Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41 , 14 20 ( 2014) DOI: 10.1016/j.immuni.2014.06.008
Ruffell B , Coussens LM : Macrophages and therapeutic resistance in cancer. Cancer Cell 27 , 462 472 ( 2015) DOI: 10.1016/j.ccell.2015.02.015
Forssell J , Oberg A , Henriksson ML , Stenling R , Jung A , Palmqvist R : High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res 13 , 1472 1479 ( 2007) DOI: 10.1158/1078-0432.CCR-06-2073
Di Caro G , Cortese N , Castino GF , Grizzi F , Gavazzi F , Ridolfi C , Capretti G , Mineri R , Todoric J , Zerbi A , Allavena P , Mantovani A , Marchesi F : Dual prognostic significance of tumour-associated macrophages in human pancreatic adenocarcinoma treated or untreated with chemotherapy. Gut 65 , 1710 1720 ( 2016) DOI: 10.1136/gutjnl-2015-309193
Malesci A , Bianchi P , Celesti G , Basso G , Marchesi F , Grizzi F , Di Caro G , Cavalleri T , Rimassa L , Palmqvist R , Lugli A , Koelzer VH , Roncalli M , Mantovani A , Ogino S , Laghi L : Tumor-associated macrophages and response to 5-fluorouracil adjuvant therapy in stage III colorectal cancer. Oncoimmunology 6 , e1342918 ( 2017) DOI: 10.1080/2162402X.2017.1342918
Garg AD , More S , Rufo N , Mece O , Sassano ML , Agostinis P , Zitvogel L , Kroemer G , Galluzzi L : Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics. Oncoimmunology 6 , e1386829 ( 2017) DOI: 10.1080/2162402X.2017.1386829
De Palma M , Lewis CE : Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23 , 277 286 ( 2013) DOI: 10.1016/j.ccr.2013.02.013
Ma Y , Galluzzi L , Zitvogel L , Kroemer G : Autophagy and cellular immune responses. Immunity 39 , 211 227 ( 2013) DOI: 10.1016/j.immuni.2013.07.017
Kroemer G , Galluzzi L , Kepp O , Zitvogel L : Immunogenic cell death in cancer therapy. Annu Rev Immunol 31 , 51 72 ( 2013) DOI: 10.1146/annurev-immunol-032712-100008
Galluzzi L , Buqué A , Kepp O , Zitvogel L , Kroemer G : Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell 28 , 690 714 ( 2015) DOI: 10.1016/j.ccell.2015.10.012
Galluzzi L , Buqué A , Kepp O , Zitvogel L , Kroemer G : Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol 17 , 97 111 ( 2017) DOI: 10.1038/nri.2016.107
Germano G , Frapolli R , Belgiovine C , Anselmo A , Pesce S , Liguori M , Erba E , Uboldi S , Zucchetti M , Pasqualini F , Nebuloni M , van Rooijen N , Mortarini R , Beltrame L , Marchini S , Fuso Nerini I , Sanfilippo R , Casali PG , Pilotti S , Galmarini CM , Anichini A , Mantovani A , D’Incalci M , Allavena P : Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 23 , 249 262 ( 2013) DOI: 10.1016/j.ccr.2013.01.008
Kodumudi KN , Woan K , Gilvary DL , Sahakian E , Wei S , Djeu JY : A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin Cancer Res 16 , 4583 4594 ( 2010) DOI: 10.1158/1078-0432.CCR-10-0733
Paulus P , Stanley ER , Schafer R , Abraham D , Aharinejad S : Colony-stimulating factor-1 antibody reverses chemoresistance in human MCF-7 breast cancer xenografts. Cancer Res 66 , 4349 4356 ( 2006) DOI: 10.1158/0008-5472.CAN-05-3523
DeNardo DG , Brennan DJ , Rexhepaj E , Ruffell B , Shiao SL , Madden SF , Gallagher WM , Wadhwani N , Keil SD , Junaid SA , Rugo HS , Hwang ES , Jirstrom K , West BL , Coussens LM : Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1 , 54 67 ( 2011) DOI: 10.1158/2159-8274.CD-10-0028
Shree T , Olson OC , Elie BT , Kester JC , Garfall AL , Simpson K , Bell-McGuinn KM , Zabor EC , Brogi E , Joyce JA : Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev 25 , 2465 2479 ( 2011) DOI: 10.1101/gad.180331.111
Jinushi M , Chiba S , Yoshiyama H , Masutomi K , Kinoshita I , Dosaka- Akita H , Yagita H , Takaoka A , Tahara H : Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc Natl Acad Sci U S A 108 , 12425 12430 ( 2011) DOI: 10.1073/pnas.1106645108
Rolny C , Mazzone M , Tugues S , Laoui D , Johansson I , Coulon C , Squadrito ML , Segura I , Li X , Knevels E , Costa S , Vinckier S , Dresselaer T , Akerud P , De Mol M , Salomaki H , Phillipson M , Wyns S , Larsson E , Buysschaert I , Botling J , Himmelreich U , van Ginderachter JA , De Palma M , Dewerchin M , Claesson-Welsh L , Carmeliet P : HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19 , 31 44 ( 2011) DOI: 10.1016/j.ccr.2010.11.009
Stockmann C , Doedens A , Weidemann A , Zhang N , Takeda N , Greenberg JI , Cheresh DA , Johnson RS : Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456 , 814 818 ( 2008) DOI: 10.1038/nature07445
Yin Y , Yao S , Hu Y , Feng Y , Li M , Bian Z , Zhang J , Qin Y , Qi X , Zhou L , Fei B , Zou J , Hua D , Huang Z : The Immune-microenvironment Confers Chemoresistance of Colorectal Cancer through Macrophage-Derived IL6. Clin Cancer Res 23 , 7375 7387 ( 2017) DOI: 10.1158/1078-0432.CCR-17-1283
Klug F , Prakash H , Huber PE , Seibel T , Bender N , Halama N , Pfirschke C , Voss RH , Timke C , Umansky L , Klapproth K , Schakel K , Garbi N , Jager D , Weitz J , Schmitz-Winnenthal H , Hammerling GJ , Beckhove P : Low-dose irradiation programs macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24 , 589 602 ( 2013) DOI: 10.1016/j.ccr.2013.09.014
Jiang W , Chan CK , Weissman IL , Kim BYS , Hahn SM : Immune Priming of the Tumor Microenvironment by Radiation. Trends Cancer 2 , 638 645 ( 2016) DOI: 10.1016/j.trecan.2016.09.007
Klopp AH , Spaeth EL , Dembinski JL , Woodward WA , Munshi A , Meyn RE , Cox JD , Andreeff M , Marini FC : Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment. Cancer Res 67 , 11687 11695 ( 2007) DOI: 10.1158/0008-5472.CAN-07-1406
Xu J , Escamilla J , Mok S , David J , Priceman S , West B , Bollag G , Mc Bride W , Wu L : CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res 73 , 2782 2794 ( 2013) DOI: 10.1158/0008-5472.CAN-12-3981
Wennerberg E , Lhuillier C , Vanpouille-Box C , Pilones KA , García-Martínez E , Rudqvist NP , Formenti SC , Demaria S : Barriers to Radiation-Induced. Front Immunol 8 , 229 ( 2017) DOI: 10.3389/fimmu.2017.00229
Bulliard Y , Jolicoeur R , Windman M , Rue SM , Ettenberg S , Knee DA , Wilson NS , Dranoff G , Brogdon JL : Activating Fc gamma receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J Exp Med 210 , 1685 1693 ( 2013) DOI: 10.1084/jem.20130573
Simpson TR , Li F , Montalvo-Ortiz W , Sepulveda MA , Bergerhoff K , Arce F , Roddie C , Henry JY , Yagita H , Wolchok JD , Peggs KS , Ravetch JV , Allison JP , Quezada SA : Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med 210 , 1695 1710 ( 2013) DOI: 10.1084/jem.20130579
Kryczek I , Zou L , Rodriguez P , Zhu G , Wei S , Mottram P , Brumlik M , Cheng P , Curiel T , Myers L , Lackner A , Alvarez X , Ochoa A , Chen L , Zou W : B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med 203 , 871 881 ( 2006) DOI: 10.1084/jem.20050930
Kuang DM , Zhao Q , Peng C , Xu J , Zhang JP , Wu C , Zheng L : Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med 206 , 1327 1337 ( 2009) DOI: 10.1084/jem.20082173
Bloch O , Crane CA , Kaur R , Safaee M , Rutkowski MJ , Parsa AT : Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clin Cancer Res 19 , 3165 3175 ( 2013) DOI: 10.1158/1078-0432.CCR-12-3314
Gordon SR , Maute RL , Dulken BW , Hutter G , George BM , Mc Cracken MN , Gupta R , Tsai JM , Sinha R , Corey D , Ring AM , Connolly AJ , Weissman IL : PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545 , 495 499 ( 2017) DOI: 10.1038/nature22396
DeNardo DG , Ruffell B : Macrophages as regulators of tumour immunity and immunotherapy. Nat Rev Immunol ( 2019) DOI: 10.1038/s41577-019-0127-6
Cottrell TR , Thompson ED , Forde PM , Stein JE , Duffield AS , Anagnostou V , Rekhtman N , Anders RA , Cuda JD , Illei PB , Gabrielson E , Askin FB , Niknafs N , Smith KN , Velez MJ , Sauter JL , Isbell JM , Jones DR , Battafarano RJ , Yang SC , Danilova L , Wolchok JD , Topalian SL , Velculescu VE , Pardoll DM , Brahmer JR , Hellmann MD , Chaft JE , Cimino-Mathews A , Taube JM : Pathologic Features of Response to Neoadjuvant Anti-PD-1 in Resected Non-Small Cell Lung Carcinoma: A Proposal for Quantitative Immune-Related Pathologic Response Criteria (irPRC). Ann Oncol ( 2018) DOI: 10.1093/annonc/mdy218
Beatty GL , Chiorean EG , Fishman MP , Saboury B , Teitelbaum UR , Sun W , Huhn RD , Song W , Li D , Sharp LL , Torigian DA , O’Dwyer PJ , Vonderheide RH : CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331 , 1612 1616 ( 2011) DOI: 10.1126/science.1198443
Vonderheide RH : The Immune Revolution: A Case for Priming, Not Checkpoint. Cancer Cell 33 , 563 569 ( 2018) DOI: 10.1016/j.ccell.2018.03.008
Clynes RA , Towers TL , Presta LG , Ravetch JV : Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med 6 , 443 446 ( 2000) DOI: 10.1038/74704
Wilson NS , Yang B , Yang A , Loeser S , Marsters S , Lawrence D , Li Y , Pitti R , Totpal K , Yee S , Ross S , Vernes JM , Lu Y , Adams C , Offringa R , Kelley B , Hymowitz S , Daniel D , Meng G , Ashkenazi A : An Fcγ receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells. Cancer Cell 19 , 101 113 ( 2011) DOI: 10.1016/j.ccr.2010.11.012
DiLillo DJ , Ravetch JV : Fc-Receptor Interactions Regulate Both Cytotoxic and Immunomodulatory Therapeutic Antibody Effector Functions. Cancer Immunol Res 3 , 704 713 ( 2015) DOI: 10.1158/2326-6066.CIR-15-0120
Herlyn D , Koprowski H : IgG2a monoclonal antibodies inhibit human tumor growth through interaction with effector cells. Proc Natl Acad Sci U S A 79 , 4761 4765 ( 1982) DOI: 10.1073/pnas.79.15.4761
Steplewski Z , Lubeck MD , Koprowski H : Human macrophages armed with murine immunoglobulin G2a antibodies to tumors destroy human cancer cells. Science 221 , 865 867 ( 1983) DOI: 10.1126/science.6879183
Adams DO , Hall T , Steplewski Z , Koprowski H : Tumors undergoing rejection induced by monoclonal antibodies of the IgG2a isotype contain increased numbers of macrophages activated for a distinctive form of antibody-dependent cytolysis. Proc Natl Acad Sci U S A 81 , 3506 3510 ( 1984) DOI: 10.1073/pnas.81.11.3506
Gordon S : Pattern recognition receptors: doubling up for the innate immune response. Cell 111 , 927 930 ( 2002) DOI: 10.1016/S0092-8674(02)01201-1
Gül N , van Egmond M : Antibody-Dependent Phagocytosis of Tumor Cells by Macrophages: A Potent Effector Mechanism of Monoclonal Antibody Therapy of Cancer. Cancer Res 75 , 5008 5013 ( 2015) DOI: 10.1158/0008-5472.CAN-15-1330
Uchida J , Hamaguchi Y , Oliver JA , Ravetch JV , Poe JC , Haas KM , Tedder TF : The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med 199 , 1659 1669 ( 2004) DOI: 10.1084/jem.20040119
Minard-Colin V , Xiu Y , Poe JC , Horikawa M , Magro CM , Hamaguchi Y , Haas KM , Tedder TF : Lymphoma depletion during CD20 immunotherapy in mice is mediated by macrophage FcgammaRI, FcgammaRIII, and FcgammaRIV. Blood 112 , 1205 1213 ( 2008) DOI: 10.1182/blood-2008-01-135160
Gennari R , Menard S , Fagnoni F , Ponchio L , Scelsi M , Tagliabue E , Castiglioni F , Villani L , Magalotti C , Gibelli N , Oliviero B , Ballardini B , Da Prada G , Zambelli A , Costa A : Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res 10 , 5650 5655 ( 2004) DOI: 10.1158/1078-0432.CCR-04-0225
Barok M , Isola J , Pályi-Krekk Z , Nagy P , Juhász I , Vereb G , Kauraniemi P , Kapanen A , Tanner M , Vereb G , Szöllösi J : Trastuzumab causes antibody-dependent cellular cytotoxicity-mediated growth inhibition of submacroscopic JIMT-1 breast cancer xenografts despite intrinsic drug resistance. Mol Cancer Ther 6 , 2065 2072 ( 2007) DOI: 10.1158/1535-7163.MCT-06-0766
Musolino A , Naldi N , Bortesi B , Pezzuolo D , Capelletti M , Missale G , Laccabue D , Zerbini A , Camisa R , Bisagni G , Neri TM , Ardizzoni A : Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol 26 , 1789 1796 ( 2008) DOI: 10.1200/JCO.2007.14.8957
Overdijk MB , Verploegen S , Bögels M , van Egmond M , Lammerts van Bueren JJ , Mutis T , Groen RW , Breij E , Martens AC , Bleeker WK , Parren PW : Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs 7 , 311 321 ( 2015) DOI: 10.1080/19420862.2015.1007813
Weng WK , Levy R : Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 21 , 3940 3947 ( 2003) DOI: 10.1200/JCO.2003.05.013
Bibeau F , Lopez-Crapez E , Di Fiore F , Thezenas S , Ychou M , Blanchard F , Lamy A , Penault-Llorca F , Frébourg T , Michel P , Sabourin JC , Boissière-Michot F : Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol 27 , 1122 1129 ( 2009) DOI: 10.1200/JCO.2008.18.0463
Chao MP , Alizadeh AA , Tang C , Myklebust JH , Varghese B , Gill S , Jan M , Cha AC , Chan CK , Tan BT , Park CY , Zhao F , Kohrt HE , Malumbres R , Briones J , Gascoyne RD , Lossos IS , Levy R , Weissman IL , Majeti R : Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142 , 699 713 ( 2010) DOI: 10.1016/j.cell.2010.07.044
Chao MP , Weissman IL , Majeti R : The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol 24 , 225 232 ( 2012) DOI: 10.1016/j.coi.2012.01.010
Willingham SB , Volkmer JP , Gentles AJ , Sahoo D , Dalerba P , Mitra SS , Wang J , Contreras-Trujillo H , Martin R , Cohen JD , Lovelace P , Scheeren FA , Chao MP , Weiskopf K , Tang C , Volkmer AK , Naik TJ , Storm TA , Mosley AR , Edris B , Schmid SM , Sun CK , Chua MS , Murillo O , Rajendran P , Cha AC , Chin RK , Kim D , Adorno M , Raveh T , Tseng D , Jaiswal S , Enger , Steinberg GK , Li G , So SK , Majeti R , Harsh GR , van de Rijn M , Teng NN , Sunwoo JB , Alizadeh AA , Clarke MF , Weissman IL : The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A 109 , 6662 6667 ( 2012) DOI: 10.1073/pnas.1121623109
McCracken MN , Cha AC , Weissman IL : Molecular Pathways: Activating T Cells after Cancer Cell Phagocytosis from Blockade of CD47 “Don’t Eat Me” Signals. Clin Cancer Res 21 , 3597 3601 ( 2015) DOI: 10.1158/1078-0432.CCR-14-2520
Gholamin S , Mitra SS , Feroze AH , Liu J , Kahn SA , Zhang M , Esparza R , Richard C , Ramaswamy V , Remke M , Volkmer AK , Willingham S , Ponnuswami A , Mc Carty A , Lovelace P , Storm TA , Schubert S , Hutter G , Narayanan C , Chu P , Raabe EH , Harsh G , Taylor MD , Monje M , Cho YJ , Majeti R , Volkmer JP , Fisher PG , Grant G , Steinberg GK , Vogel H , Edwards M , Weissman IL , Cheshier SH : Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. Sci Transl Med 9 , ( 2017) DOI: 10.1126/scitranslmed.aaf2968
Weiskopf K , Ring AM , Ho CC , Volkmer JP , Levin AM , Volkmer AK , Ozkan E , Fernhoff NB , van de Rijn M , Weissman IL , Garcia KC : Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. Science 341 , 88 91 ( 2013) DOI: 10.1126/science.1238856
Brana I , Calles A , Lo Russo PM , Yee LK , Puchalski TA , Seetharam S , Zhong B , de Boer CJ , Tabernero J , Calvo E : Carlumab, an anti-C-C chemokine ligand 2 monoclonal antibody, in combination with four chemotherapy regimens for the treatment of patients with solid tumors: an open-label, multicenter phase 1b study. Target Oncol 10 , 111 123 ( 2015) DOI: 10.1007/s11523-014-0320-2
Nywening TM , Wang-Gillam A , Sanford DE , Belt BA , Panni RZ , Cusworth BM , Toriola AT , Nieman RK , Worley LA , Yano M , Fowler KJ , Lockhart AC , Suresh R , Tan BR , Lim KH , Fields RC , Strasberg SM , Hawkins WG , DeNardo DG , Goedegebuure SP , Linehan DC : Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol 17 , 651 662 ( 2016) DOI: 10.1016/S1470-2045(16)00078-4
Pienta KJ , Machiels JP , Schrijvers D , Alekseev B , Shkolnik M , Crabb SJ , Li S , Seetharam S , Puchalski TA , Takimoto C , Elsayed Y , Dawkins F , de Bono JS : Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer. Invest New Drugs 31 , 760 768 ( 2013) DOI: 10.1007/s10637-012-9869-8
Ries CH , Cannarile MA , Hoves S , Benz J , Wartha K , Runza V , Rey-Giraud F , Pradel LP , Feuerhake F , Klaman I , Jones T , Jucknischke U , Scheiblich S , Kaluza K , Gorr IH , Walz A , Abiraj K , Cassier PA , Sica A , Gomez-Roca C , de Visser KE , Italiano A , Le Tourneau C , Delord JP , Levitsky H , Blay JY , Ruttinger D : Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25 , 846 859 ( 2014) DOI: 10.1016/j.ccr.2014.05.016
Stafford JH , Hirai T , Deng L , Chernikova SB , Urata K , West BL , Brown JM : Colony stimulating factor 1 receptor inhibition delays recurrence of glioblastoma after radiation by altering myeloid cell recruitment and polarization. Neuro Oncol 18 , 797 806 ( 2016) DOI: 10.1093/neuonc/nov272
Weizman N , Krelin Y , Shabtay-Orbach A , Amit M , Binenbaum Y , Wong RJ , Gil Z : Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase. Oncogene 33 , 3812 3819 ( 2014) DOI: 10.1038/onc.2013.357
Beatty GL , Torigian DA , Chiorean EG , Saboury B , Brothers A , Alavi A , Troxel AB , Sun W , Teitelbaum UR , Vonderheide RH , O’Dwyer PJ : A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res 19 , 6286 6295 ( 2013) DOI: 10.1158/1078-0432.CCR-13-1320
Gunderson AJ , Kaneda MM , Tsujikawa T , Nguyen AV , Affara NI , Ruffell B , Gorjestani S , Liudahl SM , Truitt M , Olson P , Kim G , Hanahan D , Tempero MA , Sheppard B , Irving B , Chang BY , Varner JA , Coussens LM : Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer. Cancer Discov 6 , 270 285 ( 2016) DOI: 10.1158/2159-8290.CD-15-0827
Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Back to top