Data from Genetically Defined Syngeneic Mouse Models of Ovarian Cancer as Tools for the Discovery of Combination Immunotherapy
Year: 2023
Type: other
Abstract: Despite advances in immuno-oncology, the relationship between tumor genotypes and response to immunotherapy remains poorly understood, particularly in high-grade serous tubo-ovarian carcinomas (HGSC). We developed a series of mouse models that carry genotypes of human HGSCs and grow in syngeneic immunocompetent hosts to address this gap. We transformed murine-fallopian tube epithelial cells to phenocopy homologous recombination–deficient tumors through a combined loss of Trp53, Brca1, Pten, and Nf1 and overexpression of Myc and Trp53R172H, which was contrasted with an identical model carrying wild-type Brca1. For homologous recombination–proficient tumors, we constructed genotypes combining loss of Trp53 and overexpression of Ccne1, Akt2, and Trp53R172H, and driven by KRASG12V or Brd4 or Smarca4 overexpression. These lines form tumors recapitulating human disease, including genotype-driven responses to treatment, and enabled us to identify follistatin as a driver of resistance to checkpoint inhibitors. These data provide proof of concept that our models can identify new immunotherapy targets in HGSC. Significance: We engineered a panel of murine fallopian tube epithelial cells bearing mutations typical of HGSC and capable of forming tumors in syngeneic immunocompetent hosts. These models recapitulate tumor microenvironments and drug responses characteristic of human disease. In a Ccne1-overexpressing model, immune-checkpoint resistance was driven by follistatin. This article is highlighted in the In This Issue feature, p. 211
Authors: Sonia Iyer, Shuang Zhang, Simge Yucel, Heiko Horn, Sean G. Smith, Ferenc Reinhardt, Esmee Hoefsmit, Bimarzhan Assatova, Julia Casado, Marie-Charlotte Meinsohn, M. Inmaculada Barrasa, George W. Bell, Fernando Pérez-Villatoro, Kaisa Huhtinen, Johanna Hynninen, Jaana Oikkonen, Pamoda M. Galhenage, Shailja Pathania, Paula T. Hammond, Benjamin G. Neel, Anniina Farkkila, David Pépin, Robert A. Weinberg
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4362567304