have patents pending. P.T.H. is a co-founder and member of the Board of Directors of LayerBio, Inc. She is on the Scientific Advisory Board of Moderna, Inc. and the Board of Directors of Alector, Inc., and she receives consulting fees and holds equity in these companies. P.T.H. is not aware of any conflicts of interest concerning the manuscript's content and topic and these entities. B.G.N. is a cofounder, holds equity in, and is a member of the Scientific Advisory Board at Navire Pharmaceuticals. He also has equity in and is a member of the Scientific Advisory Board at Avrinas, Inc. B.G.N. was an expert witness for the Johnson and Johnson ovarian cancer talc litigation in U.S. Federal Court. His spouse has equity in Amgen, Avrinas, Inc, Gilead Sciences, and Regeneron. R.A.W. is a scientific advisor for and holds an equity interest in Verastem, Inc. The other authors declare no conflicts of interest. Research.
<div>Abstract<p>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 <i>Trp53, Brca1, Pten, and Nf1</i> and overexpression of <i>Myc</i> and <i>Trp53</i><sup>R172H</sup>, which was contrasted with an identical model carrying wild-type <i>Brca1</i>. For homologous recombination–proficient tumors, we constructed genotypes combining loss of <i>Trp53</i> and overexpression of <i>Ccne1, Akt2, and Trp53</i><sup>R172H</sup>, and driven by <i>KRAS</i><sup>G12V</sup> or <i>Brd4</i> or <i>Smarca4</i> 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.</p>Significance:<p>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 <i>Ccne1</i>-overexpressing model, immune-checkpoint resistance was driven by follistatin.</p><p><i>This article is highlighted in the In This Issue feature, p. 211</i></p></div>
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