| Literature DB >> 30423296 |
Wei Wang1, Jill M Marinis2, Allison M Beal2, Shivraj Savadkar1, Yue Wu1, Mohammed Khan1, Pardeep S Taunk1, Nan Wu1, Wenyu Su1, Jingjing Wu1, Aarif Ahsan3, Emma Kurz1, Ting Chen3, Inedouye Yaboh1, Fei Li3, Johana Gutierrez1, Brian Diskin1, Mautin Hundeyin1, Michael Reilly2, John D Lich2, Philip A Harris2, Mukesh K Mahajan2, James H Thorpe2, Pamela Nassau2, Julie E Mosley2, Joshua Leinwand1, Juan A Kochen Rossi1, Ankita Mishra1, Berk Aykut1, Michael Glacken1, Atsuo Ochi1, Narendra Verma3, Jacqueline I Kim1, Varshini Vasudevaraja4, Dennis Adeegbe3, Christina Almonte3, Ece Bagdatlioglu3, Deirdre J Cohen3, Kwok-Kin Wong3, John Bertin5, George Miller6.
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.Entities:
Keywords: Pancreatic cancer; inflammation; macrophage polarization; tumor immunity
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Year: 2018 PMID： 30423296 PMCID： PMC6836726 DOI： 10.1016/j.ccell.2018.10.006
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743