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

被引：197

作者：

Wang, Wei ^{[1
]}

Marinis, Jill M. ^{[2
]}

Beal, Allison M. ^{[2
]}

Savadkar, Shivraj ^{[1
]}

Wu, Yue ^{[1
]}

Khan, Mohammed ^{[1
]}

Taunk, Pardeep S. ^{[1
]}

Wu, Nan ^{[1
]}

Su, Wenyu ^{[1
]}

Wu, Jingjing ^{[1
]}

Ahsan, Aarif ^{[3
]}

Kurz, Emma ^{[1
]}

Chen, Ting ^{[3
]}

Yaboh, Inedouye ^{[1
]}

Li, Fei ^{[3
]}

Gutierrez, Johana ^{[1
]}

Diskin, Brian ^{[1
]}

Hundeyin, Mautin ^{[1
]}

Reilly, Michael ^{[2
]}

Lich, John D. ^{[2
]}

Harris, Philip A. ^{[2
]}

Mahajan, Mukesh K. ^{[2
]}

Thorpe, James H. ^{[2
]}

Nassau, Pamela ^{[2
]}

Mosley, Julie E. ^{[2
]}

Leinwand, Joshua ^{[1
]}

Rossi, Juan A. Kochen ^{[1
]}

Mishra, Ankita ^{[1
]}

Aykut, Berk ^{[1
]}

Glacken, Michael ^{[1
]}

Ochi, Atsuo ^{[1
]}

Verma, Narendra ^{[3
]}

Kim, Jacqueline, I ^{[1
]}

Vasudevaraja, Varshini ^{[4
]}

Adeegbe, Dennis ^{[3
]}

Almonte, Christina ^{[3
]}

Bagdatlioglu, Ece ^{[3
]}

Cohen, Deirdre J. ^{[3
]}

Wong, Kwok-Kin ^{[3
]}

Bertin, John ^{[2
]}

Miller, George ^{[1
,5
]}

机构：

[1] NYU, Sch Med, Dept Surg, S Arthur Localio Lab, 435 East 30th St,4th Floor, New York, NY 10016 USA

[2] GlaxoSmithKline, Immunoinflammat Therapeut Area, Pattern Recognit Receptor Discovery Performance U, 1250 South Collegeville Rd, Collegeville, PA 19426 USA

[3] NYU, Sch Med, Dept Med, 550 First Ave, New York, NY 10016 USA

[4] NYU, Sch Med, Dept Pathol, 550 First Ave, New York, NY 10016 USA

[5] NYU, Sch Med, Dept Cell Biol, 550 First Ave, New York, NY 10016 USA

来源：

CANCER CELL | 2018年 / 34卷 / 05期

关键词：

REGULATORY T-CELLS; DENDRITIC CELLS; PROMOTES; CARCINOMA; IMMUNOTHERAPY; INFLAMMATION; NECROPTOSIS; RIPOPTOSOME; ONCOGENESIS; ACTIVATION;

D O I：

10.1016/j.ccell.2018.10.006

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 (MHCIITNF)-T-hi alpha+IFN gamma(+) 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.

引用

页码：757 / +

页数：25

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