Genetically defined syngeneic mouse models of ovarian cancer as tools for the discovery of combination immunotherapy
: Iyer Sonia, Zhang Shuang, Yucel Simge, Horn Heiko, Smith Sean G, Reinhardt Ferenc, Hoefsmit Esmee, Assatova Bimarzhan, Casado Julia, Meinsohn Marie-Charlotte, Barrasa M Inmaculada, Bell George W, Perez-Villatoro Fernando, Huhtinen Kaisa, Hynninen Johanna, Oikkonen Jaana, Galhenage Pamoda M, Pathania Shailja, Hammond Paula T, Neel Benjamin G, Färkkilä Anniina, Pépin David, Weinberg Robert A.
Publisher: American Association for Cancer Research
: 2021
: Cancer Discovery
: Cancer discovery
: Cancer Discov
: 11
: 2
: 384
: 407
: 2159-8274
: 2159-8290
DOI: https://doi.org/10.1158/2159-8290.CD-20-0818
: https://research.utu.fi/converis/portal/detail/Publication/50793807
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 p53, Brca1, Pten, Nf1, and overexpression of Myc and p53R172H, which was contrasted to an identical model carrying wild-type Brca1. For homologous recombination-proficient tumors, we constructed genotypes combining loss of p53, and overexpression of Ccne1, Akt2, p53R172H, 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.
