| Abstract [eng] |
Thesis author: Greta Šalčiūnienė Full title of the thesis: The Search for Predictive Immune Biomarkers of Epithelial Ovarian Cancer The aim of the study: To identify predictive immune biomarkers of chemotherapy resistance in the epithelial ovarian tumor microenvironment and peripheral blood, and to investigate the relationships among them. Objectives: to evaluate the suppressive/cytotoxic lymphocyte populations in patients peripheral blood; to measure the concentration of cytokines in tumor microenvironment and peripheral blood; to detect the expression of relevant immune-related genes in tumor tissue; to identify the relationships between immune-related genes expression, blood lymphocytes and concentration of cytokines in serum and tumor microenvironment, and to determine their potential predictive value of foreseeing the chemotherapy outcome. The object of the study. 36 epithelial ovarian cancer patients were involved in this study. All patients were treated in the Oncogynecology Department of National Cancer Institute during the period of 2013 – 2017. Patients were divided into chemotherapy-sensitive and resistant groups, depending on their treatment outcome. Patients’ peripheral blood, serum, tumor tissue and its lysate were collected, processed and used for ex vivo experiments. Methods. Suppressive/cytotoxic lymphocytes in the peripheral blood were subtyped by flow cytometry. Cytokine array and flow cytometry were used to measure the cytokine concentration in serum and tumor lysate. The expression of selected immune-related genes expression in the tumor tissue was analyzed by quantitative real-time PCR. Results. There were no significant differences (p>0,05) between chemotherapy-resistant and sensitive patients peripheral blood in terms of suppressive/cytotoxic lymphocyte populations. Concentrations of CCL2/MCP-1, CXCL11/I-TAC, CXCL9/MIG, CCL3/MIP-1α, CCL4/MIP-1β, IFN-γ in the blood were significantly higher (p<0,05) in treatment-resistant versus sensitive patients. However, there was no difference in cytokine concentration (p>0,05) in tumor lysates between two different groups. G-CSF and IL-1α genes were found to be upregulated (p<0,05) in chemotherapy-resistant group in comparison to sensitive patients. Our results show that correlations between various immune parameters in both groups are different (p<0,05). Conclusions. Suppressive/cytotoxic lymphocyte populations in peripheral blood are not informative enough to be used as predictive biomarkers of epithelial ovarian cancer. Elevated concentrations of CCL2/MCP-1, CXCL11/I-TAC, CXCL9/MIG, CCL3/MIP-1α, CCL4/MIP-1β, IFN-γ have the potential predictive value for selecting chemotherapy-resistant patients. However, cytokines from tumor microenvironment have no predictive power. Increased expression of G-CSF and IL-1α genes allows identifying chemotherapy-resistant patients. Correlation patterns between sensitive and resistant patients are different, suggesting that tumor development and response to treatment may depend on the specific underlying immune mechanisms, which still need to be confirmed in future studies. |
