LAUSR

Cancer-associated mesothelial cells have emerged as significant contributors to the tumor microenvironment, influencing tumor growth and immune evasion. Mesothelial cells are the first point of contact with ovarian cancer cells during peritoneal spread. Peritoneal mesothelial cells also play an essential role in immune surveillance. However, the mechanism by which cancer and mesothelial cells within the tumor microenvironment coordinate growth and immune evasion remains poorly understood. To study the role of mesothelial cells in the tumor microenvironment, we have recently generated novel syngeneic mouse models of high-grade serous ovarian cancer, which were derived from Fallopian tube epithelium, and bear human-relevant mutational genotypes. Analysis of one such model (CCNE1 amplified) using single-cell transcriptomics in omental metastases revealed specific expression of the anti-Mullerian hormone type II receptor (Amhr2) in cancer-associated mesothelial cells, whereas normal omental mesothelium does not express Amhr2. Co-culture of cancer cells with normal omental mesothelial cells induces AMHR2 expression along with a pro-tumorigenic cancer-associated mesothelial cell phenotype. Overexpression of AMHR2 in a human immortalized mesothelial cell line significantly modulated the expression of genes involved in immune response pathways, remodeling of extra-cellular matrix, and secretion of growth factors by RNAseq and qPCR. Furthermore, we showed that anti-Mullerian hormone (AMH) (the ligand of AMHR2), is secreted by ovarian cancer cells and further downregulates the chemoattractant cytokines secreted by CAMCs, thus promoting immunosuppression within the tumor. Finally, implantation of ovarian cancer cells in syngeneic Amhr2-/- hosts results in tumors that grow significantly slower than those implanted in wild-type hosts. Together these data suggest AMHR2 is a specific marker of CAMCs, whose expression is necessary for the reprogramming of mesothelial cells into CAMCs. The AMH-AMHR2 axis mediates paracrine signaling between cancer cells and CAMCs within the tumor microenvironment to promote tumor growth and immune evasion. These results suggest that AMHR2 could be a highly specific target to enhance immunotherapies in ovarian cancer. Citation Format: Maeva Chauvin. The pro-tumoral function of cancer-associated mesothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5834.