期刊
CANCER CELL
卷 34, 期 5, 页码 757-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2018.10.006
关键词
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资金
- Cancer Center support grant at the Laura and Isaac Perlmutter Cancer Center [P30CA016087]
- NIH [T32GM007308, CA168611, CA203105, CA215471, CA19311, DK106025]
- NATIONAL CANCER INSTITUTE [R01CA168611, R01CA215471, T32CA193111, P30CA016087] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK106025] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007308] Funding Source: NIH RePORTER
Pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small-molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an (MHCIITNF)-T-hi alpha+IFN gamma(+) immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T helper cell differentiation toward a mixed Th1/Th17 phenotype, leading to tumor immunity in mice and in organotypic models of human PDA. Targeting RIP1 synergized with PD1-and inducible co-stimulator-based immunotherapies. Tumor-promoting effects of RIP1 were independent of its co-association with RIP3. Collectively, our work describes RIP1 as a checkpoint kinase governing tumor immunity.
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