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

// Jacob Haagsma 1 , 2 , Yudith Ramos Valdes 1 , Xuejin Ou 3 , 4 , Rasheduzzaman Rashu 3 , S.M. Mansour Haeryfar 3 , 5 , 6 , 7 , Jim Petrik 8 and Trevor G. Shepherd 1 , 2 , 5 , 9 1 The Mary and John Knight Translational Ovarian Cancer Research Unit, Verspeeten Family Cancer Centre, London, ON, Canada 2 Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada 3 Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada 4 Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Chengdu, China 5 Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada 6 Department of Surgery, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada 7 Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada 8 Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada 9 Department of Obstetrics and Gynaecology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada Correspondence to: Trevor G. Shepherd, email: tshephe6@uwo.ca Keywords: high-grade serous ovarian carcinoma; orthotopic models; inflammation; microenvironment Received: May 27, 2025 Accepted: September 03, 2025 Published: September 22, 2025 Copyright: © 2025 Haagsma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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- Trp53 ko 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.