Immune and inflammatory signatures as predictive biomarkers of platinum response and relapse in Malaysian epithelial ovarian cancer patients

Abstract

Epithelial ovarian cancer (EOC) often exhibits chemoresistance and recurrence, complicating treatment and reducing survival. This study aimed to identify immune- related biomarkers that can predict platinum chemotherapy response and disease relapse in Malaysian women with EOC. Samples were collected from patients with EOC (n=22), benign ovarian masses (n=18), and normal controls (n=30), including blood, ovarian tissues, and ascitic fluid. A retrospective cohort analysis of high-grade serous ovarian cancer (HGSOC) tissues examined immune markers (CD4, CD8, TNFR2, STAT3, FOXP3, TIM-3) using immunohistochemistry (IHC), followed by a prospective comparison involving EOC, benign, and control samples. Serum biomarkers, including HE4, CA125, IL-6, IL-2Ra, and soluble TNFR2, were analysed using multiplex immunoassays and ELISA. Peripheral blood mononuclear cells (PBMCs) were analyzed via flow cytometry to assess T-cell immune phenotypes and their relationship to platinum response and survival. Results showed significantly elevated IL-6 levels in ascites, serum, and PBMCs in EOC patients. Immunosuppressive markers TNFR2, STAT3, and TIM-3 were highly expressed in tumour tissues, serum (sTNFR2*), and PBMCs. Teff cells showed high expression of exhaustion markers such as PD-1, CD28, and TIM-3. This immunosuppressive microenvironment led to effector T cell dysfunction and exhaustion. In vitro experiments demonstrated that the addition of a STAT3 inhibitor restored Teff proliferation, highlighting its therapeutic potential. Single-cell sequencing of PBMCs confirmed upregulation of STAT3-related genes (MYC, S100A9, S100A12) in Treg cells, while Teff cells showed an exhausted and mixed memory phenotype with high expression of CD28, TIM-3, PD-1, and GITR Although EOC showed high cytotoxic T cell (CD8") presence, platinum-resistant patients had a significantly higher CD4:CD8 ratio compared to platinum-sensitive ones. A high CD4/CD8 ratio may serve as a predictive marker for platinum resistance in EOC patients. IL-6 and STAT3-related pathways are central to immune suppression and treatment response, suggesting that IL-6 blockade and STAT3 inhibition could enhance anti-tumour immunity and improve treatment outcomes in EOC.