Abstract 1363: Cancer cell-derived exosomal microRNAs enhance immunosurveillance in long-term survivors of high-grade serous ovarian cancer

Abstract Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer-related death in the United States. The major clinical determinant to ovarian patient survival was thought to be the effectiveness of the initial debulking surgery. A more recent study in a large clinical trial, however, showed that the existence of biological differences in advanced stage EOC, including genomic signatures and tumor microenvironment (TME), determined tumor complexity and debulking status and will ultimately affect overall survival. Current studies showed that cells in TME could communicate through the exchange of microRNAs (miRs) via exosomes, which are shed or secreted by almost all cell types, to exert biological functions. As a result, our goal was to investigate the roles of miRs in modulating the activities of various cell types in the TME and identify miRs and their targets that are associated with prolonged survival rates in advanced stage EOC to allow the development of new therapeutic regimens to the disease. To identify exosomal miRs that were transferred from ovarian cancer cells to various cell types in the TME, which modulate the malignant phenotype of HGSC, exosomal miRs were isolated and quantified from nine human HGSC cell lines using miR sequencing analysis. In-situ quantification of miRs identified in exosomes in HGSC tissue sections followed by Kaplan-Meier analysis demonstrated that miR-181c-3p overexpression is associated with improved survival rate in HGSC patients. Further functional studies showed that miR-181c-3p suppresses HGSC cell growth and was correlated with intraepithelial CD8+ cytotoxic T cell (CTL) density. We identified two key immune-regulatory molecules, leukemia inhibitory factor (LIF) and Smad4, as potential direct gene targets of miR-181c-3p using online target prediction algorithms. Altering LIF expression in tumor-associated macrophages (TAMs) was also found to modulate CTL activity in the TME. These findings suggest the role of miR-181c-3p-LIF/Smad4 axis in CD8+ CTL infiltration/activation/function, and subsequently in improving HGSC patients’ survival rates. In conclusion, high-grade serous ovarian cancer (HGSC) expresses high levels of miR-181c-3p will secrete and transfer higher levels of exosomal miR-181c-3p to various cell types in the TME. The transfer of miR-181c-3p attenuates the growth promoting effects in cancer cells and endothelial cells and modulates TAMs, which will lead to increased densities of activated CD8+ CTLs in HGSC, thereby improving patients’ survival rates. Citation Format: Chi Lam Au Yeung, Marina A. Talor, Yadira J. Pacheco, Basant T. Gamal, Sammy Ferri-Borgogno, Samuel C. Mok. Cancer cell-derived exosomal microRNAs enhance immunosurveillance in long-term survivors of high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1363.