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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
Author(s) -
Li Hui,
Li Xiaoqiang,
Liu Shuang,
Guo Lei,
Zhang Bo,
Zhang Jubo,
Ye Qinghai
Publication year - 2017
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.29360
Subject(s) - cancer research , hepatocellular carcinoma , pd l1 , gene knockdown , immunotherapy , blockade , immune checkpoint , mtorc1 , effector , cell growth , cancer , ribosomal protein s6 , phosphorylation , biology , medicine , cell culture , immunology , microbiology and biotechnology , receptor , protein phosphorylation , protein kinase a , biochemistry , genetics , protein kinase b
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. (H epatology 2017;66:1920–1933)