SUMMARYThe paucity of genetically informed, immune-competent tumor models impedes evaluation of conventional, targeted, and immune therapies. By engineering mouse fallopian tube (FT) organoids using lentiviral gene transduction and/or CRISPR/Cas9 mutagenesis, we generated multiple high grade serous ovarian carcinoma (HGSOC) models exhibiting mutational combinations seen in patients. Detailed analysis of homologous recombination (HR)-proficient (Tp53-/-;Ccne1OE;Akt2OE; KrasOE), HR-deficient (Tp53-/-;Brca1-/-;MycOE) and unclassified (Tp53-/-;Pten-/-;Nf1-/-) organoids revealed differences in in vitro properties and tumorigenicity. Tumorigenic organoids had variable sensitivity to HGSOC chemotherapeutics and evoked distinct immune microenvironments. These findings enabled development of a chemotherapy/immunotherapy regimen that yielded durable, T-cell dependent responses in Tp53-/-;Ccne1OE;Akt2OE;Kras HGSOC; by contrast, Tp53-/-;Pten-/-;Nf1-/- tumors failed to respond. Genotype-informed, syngeneic organoid models could provide an improved platform for rapid evaluation of tumor biology and therapeutics.HIGHLIGHTSOrthotopic injection of genetically defined fallopian tube organoids yield HGSOC.Ovarian tumors with different genotypes evoke distinct immune microenvironmentsCombining Gemcitabine, anti-PD-L1, and anti-CTLA-4 result in complete responses in Tp53-/-;Ccne1OE;Akt2OE;KrasOE organoid-derived HGSOCTherapeutic response is tumor genotype-specific

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