期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2117754119
关键词
mouse models; ovarian cancer; cancer immunotherapy; senescence
资金
- NIH [P30 CA00874855, R01CA233944-02, R01NS114653, R21CA248106]
- Ludwig Center for Basic and Translational Immunology [GC240950]
- US Department of Defense [OC200166, OC200224]
- Mark Foundation for Cancer Research ASPIRE Award
- German Research Foundation (DFG) under Germany's excellence strategy [EXC 2180 - 390900677]
- German Academic Scholarship Foundation
- Thermo Fisher Scientific Antibody Scholarship Award
- Cancer Research Institute Irvington Fellowship
- William C. and Joyce C. O'Neil Charitable Trust
- Memorial Sloan Kettering (MSK) Single Cell Sequencing Initiative
- Edward P. Evans Foundation Young Investigator Award
- Ovarian Cancer Research Alliance Liz Tilberis Award
This study developed a fast and flexible mouse model to mimic the metastatic patterns and treatment response features of high-grade serous ovarian carcinoma. The research found that senescence propensity is a predictor of therapy response and a limited senescence-associated secretory phenotype could enhance the vulnerability of tumors to both chemotherapy and 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/STINGmediated 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据