Genetically defined syngeneic mouse models of ovarian cancer as tools for the discovery of combination immunotherapy
Reinhardt Ferenc; Bell George W; Casado Julia; Meinsohn Marie-Charlotte; Assatova Bimarzhan; Hoefsmit Esmee; Pépin David; Neel Benjamin G; Smith Sean G; Zhang Shuang; Weinberg Robert A.; Huhtinen Kaisa; Hynninen Johanna; Färkkilä Anniina; Pathania Shailja; Galhenage Pamoda M; Oikkonen Jaana; Iyer Sonia; Barrasa M Inmaculada; Perez-Villatoro Fernando; Hammond Paula T; Yucel Simge; Horn Heiko
Genetically defined syngeneic mouse models of ovarian cancer as tools for the discovery of combination immunotherapy
Reinhardt Ferenc
Bell George W
Casado Julia
Meinsohn Marie-Charlotte
Assatova Bimarzhan
Hoefsmit Esmee
Pépin David
Neel Benjamin G
Smith Sean G
Zhang Shuang
Weinberg Robert A.
Huhtinen Kaisa
Hynninen Johanna
Färkkilä Anniina
Pathania Shailja
Galhenage Pamoda M
Oikkonen Jaana
Iyer Sonia
Barrasa M Inmaculada
Perez-Villatoro Fernando
Hammond Paula T
Yucel Simge
Horn Heiko
American Association for Cancer Research
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042822266
https://urn.fi/URN:NBN:fi-fe2021042822266
Tiivistelmä
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.
Kokoelmat
- Rinnakkaistallenteet [19207]