程序性细胞死亡-1（PD-1）检查点阻断与雷帕霉素抑制剂的哺

StephenW

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,*

Version of Record online: 20 NOV 2017

DOI: 10.1002/hep.29360

© 2017 by the American Association for the Study of Liver Diseases.

Hepatology

Volume 66, Issue 6, pages 1920–1933, December 2017
Article has an altmetric score of 1

    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

    †    These authors contributed equally to this work.

Email: Qinghai Ye ([email protected])

*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)

StephenW

程序性细胞死亡-1（PD-1）检查点阻断与雷帕霉素抑制剂的哺乳动物靶点联合抑制肝癌细胞内源性PD-1诱导的肝细胞癌生长

    李辉1，李小强2，刘双1，郭磊1，张波1，张巨波3，叶青海1 *

在线记录版本：2017年11月20日

DOI：10.1002 / hep.29360

©2017由美国肝病研究协会。

肝病

第66卷，第6期，第1920-1933页，2017年12月
文章的对等评分为1

    1复旦大学附属中山医院肝癌研究所癌变与癌症侵袭重点实验室，教育部，上海
    2北京大学深圳医院胸外科，深圳，中国
    3复旦大学华山医院感染科，上海

    † 这些作者同等贡献这项工作。

Email：叶青海（[email protected]）

*地址通讯和重申要求：
叶青海博士，博士
肝癌研究所和复旦大学附属中山医院
枫林路180号
上海200032
电子邮件：[email protected]

    潜在的利益冲突：无需报告。

    国家重点基础研究发展计划（2013CB910500），国家重点攻关项目（2012ZX10002012-003），国家自然科学基金（81071993,81372654）资助。



程序性细胞死亡1（PD-1）作为单一药物的抑制剂已经导致晚期癌症患者的持久肿瘤消退。然而，只有少数癌症患者对抗PD-1免疫疗法有反应。在这里，我们表明，PD-1表达肝癌促进肿瘤生长独立的适应性免疫。 PD-1的敲减抑制肿瘤生长，而PD-1过表达增强免疫缺陷异种移植小鼠的肿瘤发生。机理上，PD-1结合雷帕霉素效应子真核起始因子4E和核糖体蛋白S6的下游哺乳动物靶，从而促进它们的磷酸化。此外，将雷帕霉素抑制的哺乳动物靶点与抗PD-1抗体治疗相结合导致比任一单一药剂更持久和协同的肿瘤消退，其中每一种药物仅呈现适度的功效。结论：靶向雷帕霉素途径的哺乳动物靶点与PD-1联用可能会增加癌症患者的抗肿瘤效果。 （Hepatology 2017; 66：1920-1933）