Abnormal epigenetic patterns correlate with effector T cell malfunction in tumors 1 – 4 . However, their causal link is unknown. Here, we show that tumor cells disrupt methionine metabolism in CD8 + T cells, thereby lowering intracellular methionine levels and the methyl donor S-adenosylmethionine (SAM), resulting in loss of H3K79me2. Consequently, loss of H3K79me2 led to low STAT5 expression and impaired T cell immunity. Mechanistically, tumor cells avidly consumed and outcompeted T cells for methionine via high expression of SLC43A2, a methionine transporter. Genetic and biochemical inhibition of tumor SLC43A2 rescued T cell H3K79me2 levels, boosting spontaneous and checkpoint-induced tumor immunity. Moreover, we found that methionine supplementation improved expression of H3K79me2 and STAT5 in T cells, accompanied by increased T cell immunity in tumor bearing models and colon cancer patients. Clinically, tumor SLC43A2 negatively correlated with T cell histone methylation and functional gene signatures. Our work reveals a novel mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumor microenvironment. Thus, cancer methionine consumption is an unappreciated immune evasion mechanism, and targeting cancer methionine signaling may provide an immunotherapeutic approach.

Summary Immunotherapies based on anti‐programmed death 1/programmed death ligand 1 (PD‐1/PD‐L1) pathway inhibitors may turn out effective in ovarian cancer (OC) treatment. They can be used in combination with standard therapy and are especially promising in recurrent and platinum‐resistant OC. There is growing evidence that the mechanism of the PD‐1/PD‐L1 pathway can be specific for a particular histological cancer type. Interestingly, the data have shown that the PD‐1/PD‐L1 pathway blockade may be effective, especially in the endometrioid type of OC. It is important to identify the cause of anti‐tumor immune response suppression and exclude its other mechanisms in OC patients. It is also necessary to conduct subsequent studies to confirm in which OC cases the treatment is effective and how to select patients and combine drugs to improve patient survival.

Ovarian cancer (OC) is usually diagnosed at an advanced stage and is related with poor prognosis. Despite numerous studies, the pathogenesis of OC is still unknown. Recent studies indicate the role of the immune system in the development and spread of OC. The identification of factors and mechanisms involved in that process and their modulation is crucial for creating effective antitumor therapy. We investigated the potential role of Th17 cells in OC patients (n = 71) by analyzing the frequencies of Th17 cells in three different environments, i.e., peripheral blood (PB), peritoneal fluid (PF), and tissue (Th17 infiltrating cells), and the concentration of IL-17A in plasma and PF of patients in terms of their clinical and prognostic significance. Th17 cells were analyzed by flow cytometry as a percentage of CD4+ lymphocytes that expressed intracellular expression of IL-17A. The level of IL-17A in plasma and PF were determined by ELISA. Our results showed accumulation of Th17 cells among tumor-infiltrating CD4+ lymphocytes (p<0.001 in relation to PB). Moreover, the percentage of Th17 cells in both PB and PF of OC patients was significantly lower than that in benign tumors group (n = 35). There were no significant differences in the percentage of Th17 cells in PB, PF, and tissue in relation to clinicopathological characteristics of OC patients and survival. The lower percentage of Th17 cells in the PB and PF of OC patients may promote evasion of host immune response by cancer cells. The concentration of IL-17A in plasma of OC patients was higher (p<0.0001) than that in both benign tumors and control group (n = 10). The PF IL-17A level in OC patients was higher (p<0.0001) than that in women with benign ovarian tumors, indicating its synthesis in OC microenvironment. Higher IL-17A level in PF is correlated with longer (median: 36.5 vs. 27 months) survival of OC patients.

The latest literature demonstrates the predominant role of the programmed cell death axis (PD-1/PD-L1/PD-L2) in ovarian cancer (OC) pathogenesis. However, data concerning this issue is ambiguous. Our research aimed to evaluate the clinical importance of PD-L1/PD-L2 expression in OC environments. We evaluated the role of PD-L1/PD-L2 in OC patients (n = 53). The analysis was performed via flow cytometry on myeloid (mDCs) and plasmacytoid dendritic cells (pDCs) and monocytes/macrophages (MO/MA) in peripheral blood, peritoneal fluid (PF), and tumor tissue (TT). The data were correlated with clinicopathological characteristics and prognosis of OC patients. The concentration of soluble PD-L1 (sPD-L1) and PD-1 in the plasma and PF were determined by ELISA. We established an accumulation of PD-L1+/PD-L2+ mDCs, pDCs, and MA in the tumor microenvironment. We showed an elevated level of sPD-L1 in the PF of OC patients in comparison to plasma and healthy subjects. sPD-L1 levels in PF showed a positive relationship with Ca125 concentration. Moreover, we established an association between higher sPD-L1 levels in PF and shorter survival of OC patients. An accumulation of PD-L1+/PD-L2+ mDCs, pDCs, and MA in the TT and high sPD-L1 levels in PF could represent the hallmark of immune regulation in OC patients.

Aim: Ovarian cancer (OC) is one of the most lethal gynecological malignancies. Recent studies suggest a crucial role of the PD-1/PD-L1 pathway in OC pathogenesis. Therefore, our study aimed at evaluation of the clinical importance of PD-1 expression in ovarian cancer patients. Patients and Methods: In this study, we investigated the role of PD-1 in OC patients (n=50) by analyzing its expression on CD4 + and CD8 + T cells in three OC environments: peripheral blood (PB), peritoneal fluid (PF), and tumor (TT) as well as soluble PD-1 (sPD-1) in plasma and PF in terms of their clinical and prognostic significance. T cells with PD-1 expression were analyzed using flow cytometry. The concentration of sPD-1 was determined with the use of ELISA. Our research demonstrated differences in PD-1 expression on CD4 + and CD8 + T cells in the OC environments. Results: We found an elevated level of CD4 + PD-1 + T cells in tumor and PF, compared to PB. Additionally, we found the highest percentage of CD8 + PD-1 + in tumor, compared to PB and PF. The levels of sPD-1 were higher (p<0.0001) in plasma than in PF. For the first time, we discovered that the higher level of CD4 + PD-1 + T cells in the circulation and the higher sPD-1 level in plasma predict poor survival of OC patients. Conclusion: We suggest that PD-1 could be a predictive biomarker for OC patients and successful immunotherapy.