2. Academic Validation
  3. RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer

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

  • Cancer Cell. 2018 Nov 12;34(5):757-774.e7. doi: 10.1016/j.ccell.2018.10.006.
Wei Wang 1,  Jill M Marinis 2,  Allison M Beal 2,  Shivraj Savadkar 1,  Yue Wu 1,  Mohammed Khan 1,  Pardeep S Taunk 1,  Nan Wu 1,  Wenyu Su 1,  Jingjing Wu 1,  Aarif Ahsan 3,  Emma Kurz 1,  Ting Chen 3,  Inedouye Yaboh 1,  Fei Li 3,  Johana Gutierrez 1,  Brian Diskin 1,  Mautin Hundeyin 1,  Michael Reilly 2,  John D Lich 2,  Philip A Harris 2,  Mukesh K Mahajan 2,  James H Thorpe 2,  Pamela Nassau 2,  Julie E Mosley 2,  Joshua Leinwand 1,  Juan A Kochen Rossi 1,  Ankita Mishra 1,  Berk Aykut 1,  Michael Glacken 1,  Atsuo Ochi 1,  Narendra Verma 3,  Jacqueline I Kim 1,  Varshini Vasudevaraja 4,  Dennis Adeegbe 3,  Christina Almonte 3,  Ece Bagdatlioglu 3,  Deirdre J Cohen 3,  Kwok-Kin Wong 3,  John Bertin 5,  George Miller 6
Affiliations

Affiliations

  • 1 S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA.
  • 2 Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
  • 3 Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
  • 4 Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
  • 5 Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. Electronic address: [email protected].
  • 6 S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA; Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. Electronic address: [email protected].
PMID: 30423296 DOI: 10.1016/j.ccell.2018.10.006
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.

Keywords

Pancreatic cancer; inflammation; macrophage polarization; tumor immunity.

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