The prognosis for ovarian cancer (OC) patients is poor and the five-year survival rate is only 47%. Immune checkpoints (ICPs) appear to be the potential targets in up-and-coming OC treatment. However, the response of OC patients to immunotherapy based on programmed cell death pathway (PD-1/PD-L1) inhibitors totals only 6–15%. The promising approach is a combined therapy, including other ICPs such as the T-cell immunoglobulin and ITIM domain/CD155/DNAX accessory molecule-1 (TIGIT/CD155/DNAM-1) axis. Preclinical studies in a murine model of colorectal cancer showed that the dual blockade of PD-1/PD-L1 and TIGIT led to remission in the whole studied group vs. the regression of the tumors with the blockade of a single pathway. The approach stimulates the effector activity of T cells and NK cells, and redirects the immune system activity against the tumor. The understanding of the synergistic action of the TIGIT and PD-1/PD-L1 blockade is, however, poor. Thus, the aim of this review is to summarize the current knowledge about the mode of action of the dual TIGIT and PD-1/PD-L1 blockade and its potential benefits for OC patients. Considering the positive impact of this combined therapy in malignancies, including lung and colorectal cancer, it appears to be a promising approach in OC treatment.

Endometriosis (EMS) is an oestrogen-dependent, chronic disease affecting women of a reproductive age. One of the important factors involved in the development of this disease is the complex disorders associated with the functioning of the immune system. Recent evidence has shown that EMS development is associated with changes in systemic and local immunity, including functional disturbances of effector and antigen-presenting cells. One of the reasons for immune imbalance can be the improper expression of immune checkpoints (ICPs). ICPs and their ligands are responsible for maintaining self-tolerance and the modulation of the initiation, duration, and magnitude of the immune response of effector cells in normal tissues to avoid tissue damage. Considering the complex nature of co-stimulatory or co-inhibitory ICPs and the signalling between effector cells and APCs, we hypothesise that changes in cells’ activity caused by ICPs may lead to serious immune system disturbances in patients with endometriosis. Moreover, both upregulation and downregulation in the expression of ICPs may be implicated in this process, including the reduced activity of effector cells against endometrial implants and disturbances in the antigen-presenting process. In this narrative review, we discuss, for the first time, key findings from the emerging literature, describing the associations between ICPs and their possible implication in the pathogenesis of endometriosis.

Endometriosis (EMS) is a common gynecological disease characterized by the presence of endometrial tissue outside the uterus. Approximately 10% of women around the world suffer from this disease. Recent studies suggest that endometriosis has potential to transform into endometriosis-associated ovarian cancer (EAOC). Endometriosis is connected with chronic inflammation and changes in the phenotype, activity, and function of immune cells. The underlying mechanisms include quantitative and functional disturbances of neutrophils, monocytes/macrophages (MO/MA), natural killer cells (NK), and T cells. A few reports have shown that immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) may promote the progression of endometriosis. MDSCs are a heterogeneous population of immature myeloid cells (dendritic cells, granulocytes, and MO/MA precursors), which play an important role in the development of immunological diseases such as chronic inflammation and cancer. The presence of MDSCs in pathological conditions correlates with immunosuppression, angiogenesis, or release of growth factors and cytokines, which promote progression of these diseases. In this paper, we review the impact of MDSCs on different populations of immune cells, focusing on their immunosuppressive role in the immune system, which may be related with the pathogenesis and/or progression of endometriosis and its transformation into ovarian cancer.

The interaction between dendritic cells (DCs) and T cells mediated by the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1)/programmed cell death ligand 2 (PD-L2) pathway is the most important point in regulating immunological tolerance and autoimmunity. Disturbances in the quantity, maturity, and activity of DCs may be involved in the implantation and growth of endometrial tissue outside the uterus in endometriosis (EMS). However, little is known about the role of the immune checkpoint pathways in EMS. In our study, we examined the expression of PD-L1/PD-L2 on myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in the peripheral blood (PB) and peritoneal fluid (PF) of both EMS patients (n = 72) and healthy subjects (n = 20) via flow cytometry. The concentration of soluble PD-L1 and PD-L2 in the plasma and PF of EMS patients and the control group were determined using ELISA. We demonstrated an elevated percentage of mDCs, mDCs and pDCs with the PD-L1or PD-L2 expression, and a higher concentration of the soluble forms of PD-L1 and PD-L2 in the PF than in the plasma of EMS patients. We conclude that the peritoneal cavity environment and the PD-1/PD-L1/PD-L2 axis may play an important role in the modulation of immune response and the development and/or progression of EMS.

Ovarian cancer (OC) is one of the deadliest gynecological cancers. Recent studies suggest a crucial role of inflammatory immune system cells in the progression and metastasis of OC. The understanding of inflammatory mechanisms is pivotal for the selection of a biomarker that allows the differentiation between malignant and benign tumors, monitoring the progression of the disease, and identification of patients that will respond to implemented treatment. Our study is aimed at evaluating the profile of IL‐6 in the plasma and peritoneal fluid (PF) of patients with various clinical manifestations of OC ( n = 78). We also examined the relationship between IL‐6 and PD‐L1/PD‐L2 positive CD45 ⁺ CD14 ⁺ inflammatory cell (MO/MA) levels in three OC environments (TME): peripheral blood (PB), PF, and tumor (TT) and their clinical and prognostic relevance in OC patients. The expression of PD‐L1/PD‐L2 molecules was analyzed by flow cytometry. The IL‐6 levels were determined by ELISA. We found an elevated level of PD‐L1/PD‐L2 positive MO/MA in TT compared to PB ( p < 0.0001). Significantly higher ( p < 0.0001) levels of IL‐6 were observed in PF of the OC patients than in the benign ovarian tumor group ( n = 31). Additionally, we found higher IL‐6 levels in PF than in the plasma of the OC patients. Interestingly, accumulation of IL‐6 was observed in PF of patients with low‐differentiated OC and correlated with worse prognosis. Moreover, we observed correlations between the level of IL‐6 and CD45 ⁺ CD14 ⁺ cells and between CD45 ⁺ CD14 ⁺ PD‐L1 ⁺ cells and the IL‐6 level in PF. For the first time, we discovered that the higher percentage of CD45 ⁺ CD14 ⁺ PD‐L2 ⁺ cells in PF predicts better survival of OC patients. Our study suggests that CD45 ⁺ CD14 ⁺ PD‐L2 ⁺ cells and IL‐6 may be predictive biomarkers for OC patients. Understanding how the composition of TME changes during OC development and progression is a prerequisite for projecting new therapeutic strategies. Overall, further validation research is warranted.

Immune system dysregulation is clinically evident in the pathogenesis of endometriosis (EMS). Changes in the dendritic cells (DCs) activity or phenotype may be involved in the implantation and growth of endometrial tissue outside the uterus in the disease. The TIM-3/Gal-9 axis is implicated in the development of immune tolerance. However, the knowledge about the exact role of this pathway in the EMS is extremely poor. In the present study, we evaluated the expression of Gal-9 on myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in the peripheral blood (PB) and peritoneal fluid (PF) of both EMS patients (n = 82) and healthy subjects (n = 10) via flow cytometry. We also investigated the concentrations of soluble Gal-9 and TIM-3 in the plasma and PF of EMS patients and the control group using ELISA. We showed significantly elevated percentages of mDCs-Gal-9⁺ and pDCs-Gal-9⁺, and significantly higher concentrations of the soluble form of Gal-9 and TIM-3 in the PF of EMS patients than in circulation. Our results led us to conclude that the accumulation of Gal-9 expressing mDCs and pDCs in the PF and high sTIM-3/Gal-9 production in the peritoneal cavity could represent the hallmark of immune regulation in EMS patients, which may augment the inflammatory process and development/maintenance of local immunosuppression.