Abstract 163: Role of macrophages in the development of ovarian cancer stem-like cells during chemotherapy

Abstract

Abstract Ovarian cancer is a poorly understood disease with 75% death rate when identified after metastasis. Drug resistance and tumor recurrence are likely due to cancer stem-like cells (CSCs) that evade chemotherapy and induce relapse with phenotypes that are distinct from bulk tumor cells. It remains unclear how CSCs facilitate relapse and what role the tumor microenvironment (TME) plays in this process. Our preliminary data show that a secreted cytokine, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), and its receptor Fn14 are overexpressed in ovarian tumors and increase after chemotherapy. TWEAK is a strong inducer of stem cell features and enhances survival of CSCs during chemotherapy exposure. The source of TWEAK has not been clarified, although clinical data from human ovarian tumors show that TWEAK mRNA was primarily observed in a subset of infiltrating immune cells known as tumor associated macrophages (TAMs). When we evaluated TWEAK expression in cells found in the ovarian TME, including PBMC and THP-1-derived macrophages, IMR-90 activated fibroblasts, and ovarian cancer cell lines, we found that PBMC macrophages were the primary source of TWEAK production. Since cytotoxic chemotherapy can enrich for different TAM populations, we propose that TWEAK producing TAMs support CSC survival and expansion and contribute to the high rate of relapse in ovarian cancer patients. We further found that treatment with a small molecule inhibitor of TAM polarization leads to decreased TWEAK production, fewer CSCs, and prolonged remission in mouse models of ovarian cancer relapse as compared to vehicle. Currently we are testing whether knockout of Fn14 in ovarian cancer cells co-cultured with TAMs reduces stem cell features dependent on TWEAK-Fn14 signaling. Identification of immune populations responsible for TWEAK production could lead to new therapeutic strategies for patients with high rates of relapse. Citation Format: Luisjesus S. Cruz, Denay Stevenson, Mikella Robinson, Steffy Mathew, Isabella Amador, Gregory Jordan, Carrie D. House. Role of macrophages in the development of ovarian cancer stem-like cells during chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 163.