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Cancer Cell. 2018 Nov 12;34(5):757-774.e7. doi: 10.1016/j.ccell.2018.10.006.

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

Author information

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: john.j.bertin@gsk.com.
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: george.miller@nyumc.org.

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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