Abstract A084: AMH paracrine signaling between cancer and mesothelial cells modulates the ovarian tumor immune microenvironment

Abstract Introduction: Cancer-associated mesothelial cells (CAMCs) have emerged as significant contributors to the tumor microenvironment, influencing tumor growth and immune evasion. Mesothelial cells represent the first point of contact of ovarian cancer cells during their peritoneal spread. Normal omental mesothelial cells have been reported to play a role in immune surveillance of the peritoneal cavity. However, beyond their initial involvement during the seeding of cancer cells to the omentum, the role of omental mesothelial cells in the subsequent development of the tumor microenvironment and the immune evasion of the tumor remains poorly understood. Methods: To study the role of mesothelial cells in the tumor microenvironment, we 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. We analysed one such model, the CCNE1-amplified KPCA cell line, using single cell transcriptomics in omental metastases to survey the pattern of expression of the anti-Müllerian hormone (Amh) and its receptor Amhr2 across tumor cell types. Results: Single-cell transcriptomics revealed specific expression of Amhr2 in cancer-associated mesothelial cells, but not normal omental mesothelium. The co-culture of cancer cells with normal omental mesothelial cells induced AMHR2 expression along with a pro-tumorigenic cancer-associated mesothelial cell transcriptomic signature. Overexpression of AMHR2 in a human immortalized mesothelial cell line (Met5a) significantly modulated the expression of genes involved in immune response pathways, remodeling of extra-cellular matrix, and secretion of growth factors. Furthermore, we showed that AMH was secreted by ovarian cancer cells and downregulated key immunomodulatory cytokines (Ccl2, Cxcl2/3, Il1a/b) secreted by CAMCs, thus promoting immunosuppression within the tumor. Finally, implantation of ovarian cancer cells into syngeneic Amhr2−/− hosts produced tumors that grew significantly slower than in wild type hosts, which contained significantly reduced populations of exhausted T cells as marked by PD1 and CTLA4 expression. Conclusion: Together these data suggest that AMHR2 expression is necessary for the reprogramming of mesothelial cells into CAMCs and represents a specific marker of CAMCs in ovarian cancer. The AMH-AMHR2 paracrine axis between cancer cells and CAMCs modulates the tumor microenvironment to promote growth and immune evasion and may represent a novel target for immunotherapy in ovarian cancer. Citation Format: Maeva Y. Chauvin. AMH paracrine signaling between cancer and mesothelial cells modulates the ovarian tumor immune microenvironment abstract. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₂): Abstract nr A084.