TY - JOUR
T1 - Genetically DEFI ned syngeneic mouse models of ovarian cancer as tools for the discovery of combination immunotherapy
AU - Iyer, Sonia
AU - Zhang, Shuang
AU - Yucel, Simge
AU - Horn, Heiko
AU - Smith, Sean G.
AU - Reinhardt, Ferenc
AU - Hoefsmit, Esmee
AU - Assatova, Bimarzhan
AU - Casado, Julia
AU - Meinsohn, Marie Charlotte
AU - Barrasa, M. Inmaculada
AU - Bell, George W.
AU - Perez-Villatoro, Fernando
AU - Huhtinen, Kaisa
AU - Hynninen, Johanna
AU - Oikkonen, Jaana
AU - Galhenage, Pamoda M.
AU - Pathania, Shailja
AU - Hammond, Paula T.
AU - Neel, Benjamin G.
AU - Farkkila, Anniina
AU - Pepin, David
AU - Weinberg, Robert A.
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/2
Y1 - 2021/2
N2 - ABstrAct Despite advances in immuno-oncology, the relationship between tumor genotypes and response to immunotherapy remains poorly understood, particularly in highgrade 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–defi cient tumors through a combined loss of Trp53, Brca1, Pten, and Nf1 and overexpression of Myc and Trp53 R172H, which was contrasted with an identical model carrying wild-type Brca1. For homologous recombination–profi cient tumors, we constructed genotypes combining loss of Trp53 and overexpression of Ccne1, Akt2, and Trp53 R172H, and driven by KRAS G12V 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.
AB - ABstrAct Despite advances in immuno-oncology, the relationship between tumor genotypes and response to immunotherapy remains poorly understood, particularly in highgrade 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–defi cient tumors through a combined loss of Trp53, Brca1, Pten, and Nf1 and overexpression of Myc and Trp53 R172H, which was contrasted with an identical model carrying wild-type Brca1. For homologous recombination–profi cient tumors, we constructed genotypes combining loss of Trp53 and overexpression of Ccne1, Akt2, and Trp53 R172H, and driven by KRAS G12V 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.
UR - https://www.scopus.com/pages/publications/85100711231
UR - https://www.scopus.com/pages/publications/85100711231#tab=citedBy
U2 - 10.1158/2159-8290.CD-20-0818
DO - 10.1158/2159-8290.CD-20-0818
M3 - Article
C2 - 33158843
AN - SCOPUS:85100711231
SN - 2159-8274
VL - 11
SP - 384
EP - 407
JO - Cancer Discovery
JF - Cancer Discovery
IS - 2
ER -