Interleukine-10 in ovarian cancer

Introduction

Ovarian cancer (OC) is the leading cause of mortality from gynecologic malignancies, with an estimated 313,959 new cases and 207,252 deaths worldwide in 2020 (1). The majority ofOC are diagnosed at an advanced stage (III or IV) (2). Generally, OC may be dichotomised into a low-grade type and a high-grade type. While the high-grade OC accounts for the majority of cases and holds P53 mutations, the low-grade type have an indolent course, are genetically stable tumors which may develop from precursor lesions, as tumor of low malignant potential or endometriosis and have frequent mutations of the KRAS, BRAF, or ERBB2 genes (3). While platinum-based combinatorial chemotherapy coupled with surgical cytoreduction reach a clinical response in the majority of patients, recurrence of tumor in the peritoneal cavity remains a major challenge for improving survival in these patients. Importantly, BRCA1/2 germline mutations are found in 6–15% of epithelial high-grade OC. BRCA1/2 carriers have a better response than non-BRCA1/2 carriers to platinum-based chemotherapies. yielding longer survival (4). Accumulating evidence suggests that inflammation plays a critical role in the tumor microenvironment (TME) in progression of cancer. Among various cytokines, interleukin 10 (IL-10) has been suggested to be involved in immune suppression and tolerance. In this review, we summarize the roles of IL-10 in OC.

OC and the peritoneal cavity

Perhaps the most unique feature of OC is its frequent association with ascites (5,6). This peritoneal fluid contains a wide spectrum of cellular and protein components, which promote tumor survival by inducing immune-evasion and immunosuppression (7). The cellular component is composed of tumor cells and non-tumor cells, including immune cells, mesothelial and endothelial cells (7). The acellular component of ascites is composed of proteins as cytokines, growth factors and metabolites contributing to tumor metastasis and chemoresistance (8,9). Importantly, the phosphoinositide 3-kinase (PI3K) pathway, which is involved in various cellular processes, including cell growth, survival, and metabolism—is frequently upregulated in epithelial OC and plays a pivotal role in preservation of genomic stability and chemoresistance (10). BRCA1/2 mutated OC, and homologous recombination (HR) deficient OC which are wild-type BRCA1/2—present a higher neo-antigen load than HR-proficient cancers, which leads to more efficient anti-tumour immune response (11).

One of the cytokines is interleukin-10 (IL-10), which contributes to an anti-inflammatory TME, that is conducive to tumor growth and chemoresistance (12). IL-10 is an anti-inflammatory cytokine, first described as cytokine synthesis inhibitory factor (13), which has been shown to play a role in OC (14). IL-10 is known to be secreted by monocytes, dendritic cells (DCs), macrophages, natural killer cells, CD4+ and CD8+ T cells, Th17 cells, B cells and OC cells themselves. Importantly, the upregulation of IL-10 expression is most pronounced in OC patients at the stage in which immune check-points, depress the activity of T cells and DCs (15,16).

Interestingly, as opposed to endometrial and cervical cancer, immunotherapies have had limited efficacy in the treatment of OC in the clinical setting (17-19). This is mostly attributed to the immunosuppressive TME within the peritoneal cavity which inhibits cytotoxic T cells function and promotes inhibitory signaling by cells and other soluble factors (20,21).

Ascites in OC, a unique immunologic environment, contains high concentrations of IL-10 (22), which is significantly higher than in OC patients’ serum (23). The role of IL-10 in this ascites TME could be to promote immunosuppression, and has become an active area of research, because it could interfere with checkpoint inhibitors (24,25). IL-10 was demonstrated to promote the anti-apoptotic effect of malignant ascites (26), and its expression correlates with a predominantly Th2 (T helper 2) cells response in advanced stage OC (27). Elevated ascites IL-10 correlated with poor prognosis in OC patients.

IL-10 and the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway

IL-10 receptor dimerization activates JAK1 and TYK2 (Figure 1), which leads to autophosphorylation. This process leads to recruitment and activation, of the transcription factor STAT3 (STAT1 and STAT5 may also be activated). The JAK/STAT signaling pathway induces the expression of important mediators of inflammation and cancer, with mounting evidence that dysregulation of the JAK/STAT pathway is associated with various cancers (28). IL-10 affects the JAK-STAT5 pathway by decreasing the phosphorylation state of STAT5 protein. Decreasing the activity of STAT5 drives the conversion of natural killer cells from cytotoxic killers to tumor promoters (29). In addition, ascites IL-10 upregulates myeloid-derived suppressor cells, which play a key immunosuppressive role in various types of cancers and in OC patients (30). This upregulation of myeloid-derived suppressor cells is promoted by triggering the STAT3 signal (31). In addition, M2-polarized macrophages in ascites from advanced OC, secrete IL-10 in response to activation of STAT3.

Figure 1 IL-10 dimerization pathway. Monomer of IL-10 molecule bilns IL-10Rα, this recruits IL-10Rβ forming a tetrameric complex from two heterodimeric IL-10 receptors. Phosphorylation and formation of JAK-STAT complex leads to changes in transcription factor expression. Figure created with BioRender.com. IL, interleukin; IL-10R, IL-10 receptor; JAK-STAT, Janus kinase/signal transducers and activators of transcription.

Factors contributing to secretion of IL-10

GATA3 pathway inducing IL-10

GATA3 is a transcription factor with a critical role in the regulation of both innate and adaptive immunity (32). GATA3 is highly expressed in the hematopoietic compartment, and is essential in the development and function of a variety of immune cells, especially T cells (33). ARID1A gene mutation is known to be present in almost half of clear cell and endometrioid OC patients (34). These mutations increase the expression of histone deacetylase 6 (HDAC6) (35) which activates proteins, as HSP90 and α-tubulin, that play pivotalrole in important cellular processes, such as cell adhesion, protein translocation, and formation of immune synapses (36). A recent study has demonstrated that GATA3 activation is increased by HDAC6 overexpression, and leads to IL-10 secretion by OC cells, affecting M2 macrophage polarization [anti-inflammatory macrophages (37)], thereby increasing immune evasion (38).

Nuclear factor kappa B (NF-κB) pathway inducing IL-10

IL-10 is transcriptionally controlled by NF-κB (39). Metadherin, a multifunctional gene associated with several tumor types, was found to be overexpressed in OC tissue (40), and to cause activation of NF-κB signaling, thereby elevating IL-10.

Pigment epithelium-derived factor (PEDF) inducing IL-10

PEDF is a 50-kDa glycoprotein of the serine protease inhibitors family (41). PEDF was found to induce production of IL-10 by immunosuppressive macrophages and supports OC cell survival in the peritoneal cavity of mice models (42).

Another study has demonstrated that Myeloid cells are the predominant producers of IL-10 in the ascites of ovarian tumor-bearing mice (43), mostly with phenotypic markers of monocytes, macrophages, and DCs. CD11b+ cells isolated from mice ascites, secreted IL-10 in significantly higher amounts than mice ID8 tumor cells.

Human OC tumor cells produce IL-10 but in limited amounts (44-46).

OC ascites IL-10 and oncological outcomes

In 1992, a seminal study by our group first identified the presence of IL-10 in the ascites of patients with OC, as compared to ascites of other causes (22), and these findings were confirmed since (42,47-50), also showing IL-10 in the serum of patients with OC (51) but at lower levels than the ascites. Later, IL-10 was found in OC tissue as compared to normal ovaries and OC cell lines (52). Monocytes which produce IL-10 in OC ascites, inhibit cytokine expression and proliferation of autologous T cells (53).

Higher concentration of IL-10 in OC ascites was associated with shorter progression free survival among OC patients (54). Patients with high levels of IL-10 in ascites showed a median progression free survival of 14 months versus 36 months for patients with low concentration of IL-10. IL-10 depletion from ascites by an IL-10 blocking antibody inhibits the survival-promoting activity of these ascites against tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), whereas the IL-10 neutralizing antibody does not affect the survival-promoting activity of an ascites that does not contain IL-10 (54). Therefore, it is suggested that IL-10 contributes to ascites-mediated TRAIL induced apoptosis inhibition. Interestingly, the inhibitory effect of the IL-10 neutralizing antibody is selective for TRAIL as it does not alter the pro survival activity of ascites against cisplatin.

Interestingly, there is one study that did not find correlation between ascites IL-10 and malignant OC, however that study included in the OC cohort also tumors of low malignant potential, and non epithelial OC, such as sex-cord and germ cell tumors (55). Moreover, this study used peritoneal washings rather than ascites, thus significantly diluting the cytokines in the peritoneal cavity (55)

OC serum IL-10 and oncological outcomes

Serum IL-10 concentration was found to be elevated in patient with OC as compared to patients with benign endometriomas. This association was found to be independently associated with a diagnosis of OC, following adjustment for age, cancer antigen 125 (CA-125), IL-6 and IL-8 serum levels (56). Similarly, multiple studies evaluating patients with benign ovarian cysts, endometriomas, and ovarian malignancies, found that serum IL-10 levels were significantly higher in OC patients than in the other study groups (49,57-61). Similarly, serum IL-10 concentration in OC patients were significantly higher than in healthy control group. Moreover, the concentration of serum IL-10 was correlated with OC stage (61-63), grade (59), and survival (64). Treatment of OC cell lines with IL-10 receptor (IL-10R) antibody, resulted in a decrease in the level of matrix metalloproteinases-2, leading to a decrease in cancer proliferation and the invasion ability (61), and IL-10 was shown to have suppressive effects on angiogenesis, tumor growth, and peritoneal dissemination of VEGF-producing OC cells (65).

The level of IL-10 significantly decreased after surgical cytoreduction in the group of patients with advanced disease and reached the level found in serum of patients with early OC (66). Similarly, following cytoreductive surgery in OC patients, there is a decrease in T_reg cell and a reduction of circulating IL-10 (67).

In another study, elevated levels of IL-10 were detected in the plasma and in the ascites of OC patients (68), with ascites IL-10 level being significantly higher than plasma.

Serum IL-10 levels decreased after chemotherapy in patients responding, while they remained elevated in non-responding to the treatment (69).

The controversial/ dual function of IL-10 in cancer

IL-10 is often referred to as having a dual role in cancer (70-89) (Table 1). Paradoxically, both IL-10-deficiency and IL-10-overexpression can promote anti-tumor immune responses in mice (90). This disparity probably reflects the significance of local TME in sculpting immune responses and the local variations in bioavailable IL-10. On the one hand, IL-10 is a potent suppressor of DC activation (91), but on the other hand, high concentrations of IL-10 can promote IL-2-dependent proliferation of CD8+ T cells (88). This has led to divergent approaches for targeting IL-10 as an anticancer therapeutic: blocking IL-10R to enhance myeloid cell function (89) versus injecting exogenous IL-10 to directly promote an anti-tumor T cell response through activation of intra-tumoral CD8+ T cells (92). Serum markers of activation of the immune system were detected when IL-10 was administered to patients (93). Pegylated IL-10 was also demonstrated to induce rejection of tumor masses in mice models, by increased CD8 + T cell-immune responses (94), and in a clinical trial on solid tumors, pegilated-IL-10 was demonstrated to be beneficial (95). CmAb-(IL-10)2, an anti-epidermal growth factor receptor (EGFR) antibody conjugated with IL-10 combined with programmed death 1 (PD-1) blockade, significantly improved antitumor effects in advanced tumors in mice (96). Furthermore, in a study among 111 patients with refractory advanced malignant solid tumors, pegylated IL-10 (Pegilodecakin) and anti-PD-1 treatment, showed significant treatment responses, suggesting that pegylated IL-10 plus anti-PD-1 monoclonal antibody may provide a new therapeutic path for previously heavily treated patients with non-small-cell carcinoma and renal cell carcinoma (95).

There is evidence that IL-10 is actually a growth-factor or has a cofactor activity, stimulating growth and differentiation in tumor cells, however this evidence is limited to B-cell tumors (97) and melanoma (86). Therefore, while IL-10 may contribute to proliferation of B cell tumors, there is little evidence supporting a general role for IL-10 as a tumor growth factor.

Overall, most evidence regarding IL-10 in the TME, indicates that IL-10 interferes with the induction or effector function of an antitumor immune response. IL-10 inhibits DC function, which may blunt induction of a response against cancer cells (98-100), and IL-10 significantly suppresses the activation of CD8 T cells in OC patients (16).

Manipulating the IL-10 signaling pathway

The TME develops in such a way that it prevents immune effector cells, mainly CD8+ T cells, from destroying tumor cells. This results in depletion of functional T cells (101,102). Immunotherapy on the other hand relies on sufficient functional T cells which are able to target the tumor, and a tumor which is immunogenic enough to attract T cells. Most immune cells express IL-10R on their membranes (103).

The first demonstration that IL-10R blockade had therapeutic efficacy in OC was provided in mice models (43). Mice that received the IL-10R blocking therapy showed significantly and substantially enhanced survival. This therapeutic efficacy of IL-10R blockade required the presence of T cells. One study analyzed the effects of standard chemotherapy coupled with IL-10 antagonists on the TME of mice harboring OC. They observed an immunosuppressive shift in the myeloid cells, with an increased expression of IL-10 shortly after chemotherapy treatment (104). Combined treatment with IL-10 antagonists significantly decreased the immunosuppressive myeloid cells population, and chemotherapy activated DCs. Coupled, combination treatment significantly increased the number of activated T and DCs as well as expression of cytotoxic factors. It was also concluded that anti IL-10 had to be administered concurrently with chemotherapy to reverse the immunosuppression caused by chemotherapy (104).

Systemic administration of IL-10R antibodies, for the purpose of blocking the IL-10 signaling pathway, triggers tumor cells to secrete more IL-10 and has as a minimal effect on tumor growth (105). Interestingly, when IL-10R antibody is administered with an intra-tumor injection of a toll-like receptor 9 ligand, there is a reversal of tumor antigen presenting cells and suppression of tumor growth in murine model (89).

Tumor vaccines necessitate an effective acute inflammation response in order the vaccine to be of benefit. Therefore, neutralizing the IL-10 produced by DCs or CD4+ T cells, generated better vaccine-mediated anti-tumor responses (106,107). Local tumor blockade of IL-10 through a nano-delivery agent, reduce the population of immunosuppressive cells, such as M2 macrophages, and programmed death ligand-1 (PD-L1)+ cells and has an anti-tumor effect (108).

However, IL-10, especially pegylated IL-10 (Pegilodecakin) suppresses cancer growth in both clinical trials and animal models, although high quality, controlled clinical trial results are yet to come (109). As most immune-associated hematopoietic cells express IL-10 receptor, respond to or secrete IL-10, the effect of IL-10 signaling manipulation on these cells needs to be further evaluated. It was shown that administration of PEG-IL-10 led to an increased infiltration of immune cell (110).

Immunization coupled with IL-10 blockade by IL-10R antibodies drastically—increase vaccine-induced antigen-specific CD8 + T cell responses (111,112). This blockade may be achieved via soluble IL-10R and IL-10R antagonist (113-115). For therapeutic antitumor vaccination, the source of IL-10 in the TME is of importance, because blockade of vaccine-induced IL-10 is more efficient than the blockade of tumor-associated IL-10 (106).

It is known that IL-10 and PD-1 effect their biological functions through various signaling pathways (116). Following a study showing that simultaneous dual blockade of IL-10 and PD-L1 is significantly more effective in restoring antiviral T cell responses in viral infection (116)—further studies in cancer were undertaken. In Melanoma patients, PD-1 blockade was shown to increase expression of IL-10R by CD8+ T cells, thereby increasing their sensitivity to the immunosuppressive effects of endogenous IL-10. IL-10 blockade strengthened the effects of PD-1 blockade in expanding CD8+ T cells and reinforcing their function. That paved the way to the rationale to block both IL-10 and PD-1 (117). Importantly, treatment of mice with ovarian tumor with PD-1 blocking antibody results in an increase in the levels of IL-10 in both ascites and serum. While monotherapy by PD-1 blockade or IL-10 neutralization was inefficient, a combination of these two led to significant improved survival and delayed tumor growth, accompanied by increased anti-tumor T cell responses (118).

In a seminal study, IL-10 was found to increase the expression of PD-1 and its ligand on OC tumor-infiltrating DCs and that this increase is STAT3 dependent (118). PD-1 blockade resulted in compensatory release of IL-10 by tumor-infiltrating DCs. Combination treatment with PD-1 blocking Ab and IL-10 neutralization/IL-10R blockade reduces tumor burden and enhances survival in tumor bearing mice. This combination blockade resulted in a robust increase in both the numbers of activated CD4⁺ and CD8⁺ T cells in the ascites of mice. Moreover, the combination blockade reduced the frequency of Myeloid derived suppressor cells in the ascites of tumor bearing mice.

Conclusions

The role of IL-10 in OC is complex. Its impact on tumor growth, immune modulation, and therapeutic responses underscores its importance as a potential target for OC treatment. A deeper understanding of IL-10’s role within the dynamic TME will aid in developing personalized and effective therapeutic strategies that leverage its dual immunosuppressive and antitumor properties. Further research and clinical trials are essential to harness the potential of IL-10 modulation in improving OC outcomes.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-23-135/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-23-135/coif). The authors have no conflicts of interest to declare.

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