Programmed cell death-1 (PD-1) checkpoint blockade in combination with a mammalian target of rapamycin inhibitor restrains hepatocellular carcinoma growth induced by hepatoma cell–intrinsic PD-1
Hui Li1,†, Xiaoqiang Li2,†, Shuang Liu1,†, Lei Guo1, Bo Zhang1, Jubo Zhang3 and Qinghai Ye1,*
Volume 66, Issue 6, pages 1920–1933, December 2017
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1 Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
2 Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen, China
3 Department of Infectious Disease, Huashan Hospital, Fudan University, Shanghai, China
*ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Qinghai Ye, M.D., Ph.D.
Liver Cancer Institute and Zhongshan Hospital, Fudan University
180 Fenglin Road
Shanghai 200032, China
E-mail: [email protected]
Potential conflict of interest: Nothing to report.
Supported by grants from the State Key Basic Research Program of China (2013CB910500), the National Key Project for Infectious Disease of China (2012ZX10002012-003), and the National Natural Science Foundation of China (81071993, 81372654).
Inhibitors of programmed cell death 1 (PD-1) administered as single agents have resulted in durable tumor regression in advanced cancer patients. However, only a minority of cancer patients respond to anti-PD-1 immunotherapy. Here, we show that PD-1 expression in hepatocellular carcinoma promotes tumor growth independently of adaptive immunity. Knockdown of PD-1 suppresses tumor growth, whereas PD-1 overexpression enhances tumorigenesis in immunodeficient xenografted mice. Mechanistically, PD-1 binds the downstream mammalian target of rapamycin effectors eukaryotic initiation factor 4E and ribosomal protein S6, thus promoting their phosphorylation. Moreover, combining mammalian target of rapamycin inhibition with anti-PD-1 antibody treatment results in more durable and synergistic tumor regression than either single agent alone, each of which presents only modest efficacy. Conclusion: Targeting mammalian target of rapamycin pathways in combination with PD-1 may result in increased antitumor efficacy in cancer patients. (Hepatology 2017;66:1920–1933) 作者: StephenW 时间: 2017-11-23 15:06