| First Author | Wang W | Year | 2018 |
| Journal | Cancer Cell | Volume | 34 |
| Issue | 5 | Pages | 757-774.e7 |
| PubMed ID | 30423296 | Mgi Jnum | J:266849 |
| Mgi Id | MGI:6256872 | Doi | 10.1016/j.ccell.2018.10.006 |
| Citation | Wang W, et al. (2018) RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer. Cancer Cell 34(5):757-774.e7 |
| abstractText | 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 MHCII(hi)TNFalpha(+)IFNgamma(+) 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. |
