Cancer Cell
Volume 34, Issue 5, 12 November 2018, Pages 757-774.e7
Journal home page for Cancer Cell

Article
RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer

https://doi.org/10.1016/j.ccell.2018.10.006Get rights and content
Under an Elsevier user license
open archive

Highlights

  • RIP1 promotes tolerogenic macrophage differentiation via suppression of STAT1 in cancer

  • GSK′547 (RIP1i) is a mono-selective kinase inhibitor that robustly targets RIP1 in vivo

  • RIP1i is tumor-protective via macrophage-mediated Th1/Th17 and CTL activation

  • RIP1i synergizes with checkpoint- and co-stimulatory receptor-based immunotherapies

Summary

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 MHCIIhiTNFα+IFNγ+ 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.

Keywords

Pancreatic cancer
macrophage polarization
inflammation
tumor immunity

Cited by (0)

6

These authors contributed equally

7

Senior author

8

Lead Contact