Loss of <i>Trp53</i> 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
Bibliographic record
Abstract
// 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".