Ovarian cancer is highly lethal; its overall prognosis has remained poor over the past few decades [10]. Two-thirds of affected patients have advanced disease, and the majority of them will experience disease relapse requiring continuous treatment; many of these patients will die of the disease [11].

Prognostic factors defined by correlation with survival generally reflect the extent of the disease (staging), the intrinsic biology of the tumor (type and histological grade), and the patient’s ability to tolerate treatment of the disease. In addition to these pre-treatment factors, others that may affect survival include the type of treatment received (e.g., optimal debulking, chemotherapy based on platinum derivatives) and the effects of the therapy on the tumor (e.g., complete response, other) and the patient (e.g., myelosuppression) [12]. Among these prognostic factors, the International Federation of Gynecology and Obstetrics staging is considered to be the most important [4], followed by the presence of residual disease after surgery and the initial histological type and tumor grade. Several groups have evaluated the clinical relevance of different biological variables in tissue and serum samples from patients with ovarian cancer in the effort to identify biomarkers capable of predicting the response to chemotherapy or patient survival. Studies of the roles of individual molecular markers have demonstrated that ovarian carcinogenesis is a complex, multifactorial process associated with abnormalities in several families of genes, which could have predictive or prognostic relevance [13]. Primary cytoreductive surgery followed by adjuvant chemotherapy remains the standard treatment for patients with ovarian cancer. However, the survival rate varies considerably among patients with the same pathological stage of disease receiving the same treatment, which may be attributable to host-related factors, including variations in the inflammatory response [14].

The identification of new biomarkers for the diagnosis and prognosis of ovarian cancer, which ideally also serve as targets for new therapeutic modalities, is urgently needed [15]. Transvaginal ultrasound and cancer antigen 125 (cancer antigen 125 (CA-125)) detection are used commonly to detect ovarian cancer [16]. Over time, the use of a combination of biomarkers (carcinoembryonic antigen, carbohydrate antigen 19-9, and Human Epididymis protein 4) together with CA-125 has emerged, but no biomarker in clinical use for the early detection of ovarian cancer is fully effective due to a lack of sensitivity or specificity [17]. In the future, the identification of new biomarkers will also aid the identification of specific markers for molecular targeted therapy [18].

In recent years, laboratory-quantified systemic inflammatory response markers, such as hypoalbuminemia, hyperfibrinogenemia, the C-reactive protein level, the absolute leukocyte count, the neutrophil/lymphocyte ratio (NLR), and the platelet/lymphocyte ratio (PLR), have been introduced as prognostic factors for various types of cancer, including ovarian cancer [14, 19]. The NLR and PLR have recently been shown to be significant predictors of malignancy for solid tumors originating from various tissues; they are also useful in screening for these tumors, as they can be determined using inexpensive and readily available tests [20]. However, the authors reporting on this research indicated the need for further assessment of the additional value of these findings, the establishment of scores, and the determination of the potential predictive value of these markers for gynecological cancers [20]. Sanguinete et al. [21] demonstrated that increased levels of interleukin (IL)-6 and IL-8, observed in the more advances stages of ovarian cancer, were associated with better prognoses. Various theories have been proposed to explain the function of the immune system in relation to tumor cells and their respective signaling molecules. IL levels are found in patients with ovarian cancer related to prognostic factors [21, 22, 23].

The pathophysiology of ovarian cancer is complex and remains poorly understood. Its diagnosis is affected greatly by the absence of specific signs and symptoms, the lack of reliable biomarkers, and the anatomical location of the ovaries. Thus, ovarian cancer is often diagnosed in the advanced stage of the disease, rendering its prognosis uncertain [24] and of limited value. Thus, researchers have sought to identify means by which to improve the prognosis of the disease and better guide its therapeutic management [25].

The host immune system interacts with tumor development, and in some cases may be responsible for the delay of tumor growth or progression. Chronic inflammation has been identified as a key factor in the pathogenesis of ovarian cancer [26]. Ovulation is a potentially inflammatory and mutagenic process [27]. Most tumors have complex relationships with their hosts, with the presence of inflammatory cells and mediators in the tumor microenvironment resulting in the production of chemokines, cytokines, and prostaglandins, which recruit inflammatory cells (e.g., neutrophils, mast cells, and macrophages) and stimulate angiogenesis and cell proliferation [28, 29]. In addition, tumors can evade immunovigilance, resulting in a certain degree of tolerance by the immune system, and their ability to interfere with immune cell function seems to be the main reason for the failure to control tumor progression [30].

Inflammation influences all stages of cancer development, including tumor initiation, promotion, and progression [26]. Several inflammatory mediators are induced by inflammatory and/or tumor cells and participate in the development of cancer, acting as growth or angiogenic factors. In addition, immune function is compromised by these mediators, causing increases in the levels of leukocytes, neutrophils, platelets, C-reactive protein, and fibrinogen, and reducing the concentrations of lymphocytes and albumin. Cancer-induced thrombocytosis can significantly increase the number of circulating platelets, by mechanisms that remain poorly understood [31]. A multicenter study conducted by Stone et al. [32] showed that thrombocytosis is associated significantly with poor prognosis and directly influences patient survival. In addition, that study revealed that the inflammatory cytokine IL-6 influences thrombocytosis in patients with ovarian cancer by stimulating hepatic thrombopoietin synthesis [32].

Adaptive and innate immune responses, including cytotoxic and antibody secretion processes, are dysfunctional in patients with cancer, which can increase susceptibility to cancer cell growth and invasion and thus to tumor development [33, 34]. An escape mechanism that favors the maintenance of ovarian cancer is the triggering of an imbalance in T helper 1 (Th1) and T helper 2 (Th2) responses, with an increase in the latter that results in impairment of the processes that control homeostasis in the tumor microenvironment [35]. The Th1-type immune response stimulates cellular immunity by activating macrophages and dendritic cells and recruiting cluster of differentiation 8+ (CD8+) cytotoxic T (Tc) cells and natural killer (NK) cells. The Th2-type immune response inhibits cell-mediated immunity and favors the humoral immune response. The generation of a Th1- or Th2-type immune response depends on the cytokine balance [36]. Increasing evidence indicates that T cell activation and the resulting cytokine expression play key roles in the diminution and disruption of inflammatory and antitumor immune responses [37].

The environment in which ovarian carcinoma develops has been described as large and rich in proinflammatory cytokines and chemokines. This tumor produces IL-1$\beta$, IL-6, and IL-12, which in addition to the stimulation of cancer cell growth are responsible for the creation of a microenvironment promoting cell proliferation and tumor growth, thereby directly affecting the severity of inflammation [38]. The unbalanced production of Th1 and Th2 cytokines can favor changes in the secretion of pro-inflammatory cytokines and consequently aggravate tumor progression [39]. Sanguinete et al. [21] demonstrated that increased IL-6 and IL-8 levels were associated with a worse prognosis of ovarian cancer.

Several elements of the immune response to ovarian cancers have prognostic significance. The presence of different leukocyte populations infiltrating or associated with the tumor has been correlated with better and worse prognoses of the disease, indicating the protective and, at the same time, promoter of the immune system against cancer [40, 41, 42, 43].

Studies performed with various tumor tissues have demonstrated strong infiltration of leukocytes into the intratumoral and peritumoral regions. The presence of these cells is related to responses to tumors, due to pre-cancer inflammatory processes or by substances produced by the tumor cells [44]. Their detection in ovarian tumors enables better prediction of clinical outcomes than achieved with the use of other histopathological parameters, indicating that the immunological profile can be useful in conducting alternative forms of treatment, such as immunotherapy [24, 45].

In patients diagnosed with advanced-stage ovarian cancer, the NK cell level in the peripheral blood is significantly higher than those in the tumor and ascites [51]. Increased numbers of NK cells in ascites have been related to worse clinical outcomes of ovarian cancer and decreased survival [52]. CA-125 can reduce the cytolytic capacity of NK cells by up to 70%. It binds to NK cells, especially to CD16+CD56+ NK cells, which comprise about 90% of the NK cells present in the peripheral blood [53].

Tumor-associated macrophages (TAMs) affect various aspects of neoplastic tissues, such as their vascularization, growth rate, formation, and stroma dissolution [54]. Macrophages constitute about 51% of the population of mononuclear cells infiltrated into ovarian carcinomas; they have been observed in all malignant tumors and 57% of benign tumors, with their average number being significantly higher in the former than in the latter [48].

The survival of tumor cells that metastasize from primary tumors to secondary sites depends on the stromal microenvironment. This metastatic growth occurs primarily with the formation of a pre-metastatic niche before the macroscopic invasion of tumor cells. Exosomes, which are small extracellular vesicles that prepare a distant tumor microenvironment for metastatic invasion, are released from a primary ovarian tumor and regulate communication among tumor cells in the normal stroma, cancer-associated fibroblasts (CAFs), and local immune cells in the tumor microenvironment to support the viability of tumor cells and metastatic dissemination. Functionally, they reprogram stromal cells in the pre-metastatic niche, including CAFs and pericytes. Exosomes also interact with TAMs in the metastatic microenvironment, which are responsible for tumor growth, invasion, angiogenesis, and general metastasis [55].

TAMs are capable of producing matrix metalloproteinases that can be pro- and anti-angiogenic molecules [56]. TAMs of the M1 and M2 types are responsible for the suppression and promotion of cancer progression, respectively [57].

In the tumor microenvironment, the interaction between endothelial cells and pericytes causes angiogenic support of the tumor [58].

CAFs are groups of cells with a reactive common fibroblast phenotype that are induced by cancer cells. This dynamics between CAFs and tumor cells stimulate cancer cells to produce factors that support and activate CAFs, resulting in the promotion of angiogenic events, cellular proliferation, remodeling of the extracellular matrix, and tumor progression [59]. The resulting changes in stromal components further exacerbate the tumorigenic microenvironment and facilitate oncogenic transformation, tissue invasion, and metastasis during cancer onset and progression [60].

Cancer immunotherapy involves the use of different approaches to improve the ability of an individual’s immune system to eliminate tumor cells [61]. Current immunotherapy types can be classified as active and passive. Active immunotherapy consists of the stimulation of the immune response against tumor antigens. It can be nonspecific, involving the administration of substances that stimulate and restore the immune system, or specific, i.e., related to tumor vaccines. Active specific immunotherapy can be autologous, performed with vaccines and serums produced from the patient’s cell culture, or heterologous, in which these substances are produced from the cells of another patient with a similar neoplasm. Passive immunotherapy consists of the administration of anti-tumor antibodies or effector cells against a certain type of tumor [62].

Trials designed to improve our understanding of the role of active immunotherapy in the treatment of ovarian cancer have been based on the premise that activation of the immune system, which would trigger a more robust immune response with the ability to attack tumor cells and induce apoptosis, would lead to increased tumor clearance. Five main active approaches to immune system sensitization to anti-tumor vaccines are currently used. The first approach is the administration of mesothelin, a protein overexpressed in many ovarian cancers; although clinical studies have shown that patients tolerate this treatment well, no conclusion regarding its effectiveness in the treatment of ovarian cancer has been drawn [63]. The second approach is the administration of a vaccine targeting the New York esophageal squamous cell carcinoma 1 (NY-ESO-1) protein. Differential expression of this antigen has been demonstrated in many ovarian tumors compared with that in normal tissues, and has the function of inducing CD4 and CD8. As a result, patients have improved survival after NY-ESO-1 vaccination [64]. The third approach is the administration of a vaccine containing the tumor suppressor gene p53. Ovarian cancer often expresses a mutant form of p53 early in its development, making it a potential target for immunotherapy. Although evidence supports the safety of this vaccine, its effectiveness has not been determined [65]. The fourth approach is the administration of a vaccine that targets the (Wilms’ tumor 1) WT1 and Human Epidermal growth factor Receptor 2 (HER2) antigens. These antigens are particularly attractive as targets due to the frequency with which they are found in ovarian cancer and to the association of HER2 expression with the most aggressive phenotype of the tumor. Vaccines with both antigens have shown promise, but data on their effectiveness from a large prospective randomized controlled trial are lacking [66]. The fifth approach is the administration of vaccines based on dendritic cells. Preclinical studies have shown that dendritic cells exposed to ovarian tumor lysates activate T cells [67], suggesting that therapy with dendritic cells improves tumor-related immune responses. Data on the effectiveness of this treatment from large robust clinical trials are not yet available [68].

Immunological checkpoints constitute a multitude of inhibitory pathways connected to the immune system. Their function is to maintain self-tolerance and the regulation of the timing and amplitude of physiological immune responses in peripheral tissues, to decrease collateral damage to tissue after a response to pathogens. The action of checkpoints in the immune system begins with ligand–receptor interaction, which can be blocked easily with antibodies or modulated with recombinant forms of ligands or receptors [69]. Checkpoint blocking is of great interest in cancer research and is a very promising approach to the improvement of anti-tumor immunity in patients with ovarian cancer. Molecules such as programmed cell death protein 1 (PD-1), cytotoxic antigen associated with the T4 lymphocyte (CTLA-4), lymphocyte activation gene-3, T-cell immunoglobulin, and mucin-3 protein have been targeted in studies of immunological checkpoints [70]. In the context of clinical immunotherapy for cancer, the two most-studied checkpoint-blocking receptors are CTLA-4 (CD152) and PD-1 (CD279); monoclonal antibodies targeting CTLA-4 (binding to CD80/86) and PD-1 or its ligand (PD-L1) have been investigated in several clinical trials [69].

The US Food and Drug Administration has approved six checkpoint inhibitors: ipilimumab (a CTLA-4 antibody); pembrolizumab and nivolumab (PD-1 antibodies); and avelumab, atezolizumab, and durvalumab (PD-L1 antibodies) [71]. Although anti–CTLA-4 and anti–PD-1/PD-L1 antibodies increase the anti-tumor immune response by increasing the number of T cells that infiltrate the tumor and restoring the effector function of Tc cells, their mechanisms of action differ [69].

CTLA-4 (CD152) is present specifically on T cells and shares a set of ligands with the CD28 costimulatory receptor. CD28 and CTLA-4 share two equal ligands: B7.1 (CD80) and B7.2 (CD86). Although disputes occur between these receptors regarding binding to B7.1 and B7.2, CTLA-4 has much greater affinity for both ligands, thus providing for competitive inhibition [69]. Antibodies against CTLA-4 block its ligand binding, thereby increasing CD28-mediated costimulation. CTLA-4 blockade enhances the proliferation and activation of tumor-specific CD8+ T cells [72] and promotes an increase in immune responses that are dependent on Th cells, increasing their suppressive function. The specific CTLA-4 blockade of Treg cells significantly inhibits the ability to regulate autoimmune and anti-tumor immunity [69].

PD-1 is expressed on T cells and inhibits T-cell activity in the effector phase [73]. After activation by its ligands PD-L1 (B7-H1 and CD274) and PD-L2 (B7-CD and CD273), PD-1 recruits the inhibitory phosphatase SHP-2, which rapidly dephosphorylates CD28 and inactivates its costimulatory signaling [74]. Of the two PD-1 ligands, PD-L1 is considered to be the most relevant in the tumor microenvironment due to its expression in tumor, stromal, and immunological cells [75]. Antibodies against PD-1 and PD-L1 restore the function of tumor-infiltrating T cells, favoring tumor regression [76].

Antibodies targeting PD-1, PD-L1, and CTLA-4 have been tested in patients with recurrent ovarian cancer. In general, response rates range from 5.9% to 15% [77]. Anti–CTLA-4 activity yielded greater toxicity and lower response rates than did assays with monoclonal anti–PD-1/PD-L1 antibodies [78].

The main barrier to the success of immunotherapy for patients with ovarian cancer remains the immunosuppressive tumor microenvironment. Checkpoint blockade alone may not be sufficient. Although immunotherapy may generate a large number of tumor-specific T cells, these cells do not always destroy tumor targets easily in vivo, meaning that additional treatment pathways should be studied to improve the effectiveness of the antitumor immune response [79].

The combined use of immunological checkpoint blockers with other immunological inhibitors, such as poly(ADP-ribose) polymerase (PARP) and vascular endothelial growth factor (VEGF) inhibitors, has resulted in progress in immunotherapy for ovarian cancer. PARP inhibitors are used in the treatment of advanced epithelial ovarian cancers with BRCA 1–2 gene mutation. They block base excision repair in cancer cells lacking homologous recombination due to BRCA mutation, resulting in the activation of the synthetic lethality mechanism, with the loss of DNA repair and cell death [80]. The combined use of PARPi olaparib and anti-PD-L1 durvalumab showed modest clinical activity in recurrent ovarian cancer [81]. Vascular endothelial growth factor (VEGF) is known mainly as a mediator of angiogenesis and immune suppression in the tumor microenvironment. Inhibitors targeting VEGF or its receptors reduce the numbers of Treg cells and myeloid-derived suppressor cells and increase the infiltration of effector T cells [82].

Checkpoint blockers have been combined with chemotherapy to enhance the anti-tumor immune response, induce direct cytotoxic effects on tumor cells and immunogenic cell death, increase antigen presentation, and alter the inflammatory tumor medium [83]. Five phase III randomized controlled trials examining the addition of PD-L1 blockade to chemotherapy are currently underway; avelumab is being used in two trials and atezolizumab is being used in three trials. The use of durvalumab and a PD-1 inhibitor in combination with chemotherapy is being tested in several phase I/II clinical trials. Based on published results, combined treatment with PD-1/PD-L1 inhibitors and chemotherapy is potentially superior to chemotherapy alone [84].

Adoptive cell therapy (ACT) against ovarian tumors is also being studied. Adoptive immunotherapy is emerging as an active treatment for cancers that are less responsive or resistant to treatment with checkpoint blockers. This approach is based on the infusion of autologous or allogeneic immune effectors that destroy tumor cells. One of the most promising approaches for the treatment of solid tumors involves tumor-specific Tc cells isolated from the tumor or peripheral blood, which are expanded ex vivo and then infused after lympho-depleting chemotherapy. Two main forms of ACT are currently being used in cancer therapy: TIL isolation and expansion, and the use of genetically engineered T cells that express a specific tumor antigen receptor or chimeric antigen receptor [83].