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
  • 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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