LAUSR

Significance Efforts to understand and find new treatment options for high-grade serous ovarian cancer (HGSOC) have been confounded by a paucity of immune-competent models that accurately reflect the genetics and biology of the disease. Here, we leverage somatic tissue engineering to develop a fast and flexible immune-competent mouse model of HGSOC and reveal mechanistic insights into factors that dictate the response of ovarian tumors to conventional chemotherapy and immune checkpoint blockade. Our results identify a genotype-dependent therapy-induced senescence program that mediates sensitivity and resistance to first line chemotherapy and point to strategies to harness the senescence program to sensitize ovarian tumors to immune checkpoint blockade. High-grade serous ovarian carcinoma (HGSOC) is a cancer with dismal prognosis due to the limited effectiveness of existing chemo- and immunotherapies. To elucidate mechanisms mediating sensitivity or resistance to these therapies, we developed a fast and flexible autochthonous mouse model based on somatic introduction of HGSOC-associated genetic alterations into the ovary of immunocompetent mice using tissue electroporation. Tumors arising in these mice recapitulate the metastatic patterns and histological, molecular, and treatment response features of the human disease. By leveraging these models, we show that the ability to undergo senescence underlies the clinically observed increase in sensitivity of homologous recombination (HR)–deficient HGSOC tumors to platinum-based chemotherapy. Further, cGas/STING-mediated activation of a restricted senescence-associated secretory phenotype (SASP) was sufficient to induce immune infiltration and sensitize HR-deficient tumors to immune checkpoint blockade. In sum, our study identifies senescence propensity as a predictor of therapy response and defines a limited SASP profile that appears sufficient to confer added vulnerability to concurrent immunotherapy and, more broadly, provides a blueprint for the implementation of electroporation-based mouse models to reveal mechanisms of oncogenesis and therapy response in HGSOC.