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

Wei Wang, Jill M. Marinis, Allison M. Beal, Shivraj Savadkar, Yue Wu, Mohammed Khan, Pardeep S. Taunk, Nan Wu, Wenyu Su, Jingjing Wu, Aarif Ahsan, Emma Kurz, Ting Chen, Inedouye Yaboh, Fei Li, Johana Gutierrez, Brian Diskin, Mautin Hundeyin, Michael Reilly, John D. LichPhilip A. Harris, Mukesh K. Mahajan, James H. Thorpe, Pamela Nassau, Julie E. Mosley, Joshua Leinwand, Juan A. Kochen Rossi, Ankita Mishra, Berk Aykut, Michael Glacken, Atsuo Ochi, Narendra Verma, Jacqueline I. Kim, Varshini Vasudevaraja, Dennis Adeegbe, Christina Almonte, Ece Bagdatlioglu, Deirdre J. Cohen, Kwok Kin Wong, John Bertin, George Miller

Research output: Contribution to journalArticlepeer-review

156 Scopus citations

Abstract

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. Wang et al. synthesize a selective RIP1 inhibitor that can be used in vivo. Inhibition of RIP1, which is highly expressed in tumor-associated macrophages in pancreatic ductal adenocarcinoma, reverses local immune suppression and enhances the efficacy of checkpoint- and co-stimulatory receptor-based immunotherapy.

Original languageEnglish
Pages (from-to)757-774.e7
JournalCancer Cell
Volume34
Issue number5
DOIs
StatePublished - Nov 12 2018

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

  • Pancreatic cancer
  • inflammation
  • macrophage polarization
  • tumor immunity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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