Loss of Trp53 results in a hypoactive T cell phenotype accompanied by reduced pro-inflammatory signaling in a syngeneic orthotopic mouse model of ovarian high-grade serous carcinoma.

Abstract

Ovarian high-grade serous carcinoma (HGSC) is an aggressive disease with an urgent need for improved therapies. Immunotherapies have proved useful for some cancers but have failed to provide benefits for HGSC. Improving our understanding of the mechanisms regulating the HGSC tumor microenvironment will facilitate the discovery of novel immunotherapies and help predict patient response. To this end, the development of syngeneic models is imperative to recapitulate immune responses observed in patients with HGSC. Yet, few syngeneic HGSC mouse models exist that accurately reflect the initiation and disease progression of human disease. In this study, we developed a syngeneic model reflecting both the site of origin and the genotype of early HGSC disease by deleting Trp53 in mouse oviductal epithelial (OVE) cells. Orthotopic injection of OVE cells demonstrated advanced disease progression due to loss of Trp53, associated with a less active T cell phenotype. Molecular analyses uncovered altered inflammatory signaling in OVE4-Trp53ko cells. Further analysis on an ascites-derived cell line identified selection for decreased pro-inflammatory signaling. These results highlight potential mechanisms by which loss of p53 function contributes to an immunosuppressive microenvironment in HGSC, and provide insight into the role of ovarian and peritoneal microenvironments in regulating HGSC cell-intrinsic inflammatory signaling.