Genetically Defined Syngeneic Mouse Models of Ovarian Cancer as Tools for the Discovery of Combination Immunotherapy
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 01, 2021
- Source ID
- 10.1158/2159-8290.cd-20-0818
Entities
People
- Anniina Färkkilä
- Benjamin G. Neel
- Bimarzhan Assatova
- David Pépin
- Esmee Hoefsmit
- Ferenc Reinhardt
- Fernando Pérez-Villatoro
- George W Bell
- Heiko Horn
- Jaana Oikkonen
- Johanna Hynninen
- Julia Casado
- Kaisa Huhtinen
- M. Inmaculada Barrasa
- Marie-charlotte Meinsohn
- Pamoda M. Galhenage
- Paula T. Hammond
- Robert Weinberg
- Sean G. Smith
- Shailja Pathania
- Shuang Zhang
- Simge Yucel
- Sonia Iyer
Organizations
- Harvard Medical School
- Massachusetts Institute of Technology
- National Institutes of Health
- University of Helsinki
- University of Massachusetts
- University of Turku