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RIP1 kinase drives macrophage-mediated adaptive immune tolerance in pancreatic cancer

DOI: 10.1016/j.ccell.2018.10.006 DOI Help

Authors: Wei Wang (New York University School of Medicine) , Jill M. Marinis (GlaxoSmithKline) , Allison M. Beal (GlaxoSmithKline) , Shivraj Savadkar (New York University School of Medicine) , Yue Wu (New York University School of Medicine) , Mohammed Khan (New York University School of Medicine) , Pardeep S. Taunk (New York University School of Medicine) , Nan Wu (New York University School of Medicine) , Wenyu Su (New York University School of Medicine) , Jingjing Wu (New York University School of Medicine) , Aarif Ahsan (New York University School of Medicine) , Emma Kurz (New York University School of Medicine) , Ting Chen (New York University School of Medicine) , Inedouye Yaboh (New York University School of Medicine) , Fei Li (New York University School of Medicine) , Johana Gutierrez (New York University School of Medicine) , Brian Diskin (New York University School of Medicine) , Mautin Hundeyin (New York University School of Medicine) , Michael Reilly (GlaxoSmithKline) , John D. Lich (GlaxoSmithKline) , Philip A. Harris (GlaxoSmithKline) , Mukesh K. Mahajan (GlaxoSmithKline) , James H. Thorpe (GlaxoSmithKline) , Pamela Nassau (GlaxoSmithKline) , Julie E. Mosley (GlaxoSmithKline) , Joshua Leinwand (New York University School of Medicine) , Juan A. Kochen Rossi (New York University School of Medicine) , Ankita Mishra (New York University School of Medicine) , Berk Aykut (New York University School of Medicine) , Michael Glacken (New York University School of Medicine) , Atsuo Ochi (New York University School of Medicine) , Narendra Verma (New York University School of Medicine) , Jacqueline I. Kim (New York University School of Medicine) , Varshini Vasudevaraja (New York University School of Medicine) , Dennis Adeegbe (New York University School of Medicine) , Christina Almonte (New York University School of Medicine) , Ece Bagdatlioglu (New York University School of Medicine) , Deirdre J. Cohen (New York University School of Medicine) , Kwok-kin Wong (New York University School of Medicine) , John Bertin (GlaxoSmithKline) , George Miller (New York University School of Medicine)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Cancer Cell , VOL 34 , PAGES 757 - 774.e7

State: Published (Approved)
Published: November 2018

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.

Journal Keywords: Pancreatic cancer; macrophage polarization; inflammation; tumor immunity; tumour

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography