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)

中文翻译：

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程序性细胞死亡1（PD-1）检查点封锁与哺乳动物雷帕霉素抑制剂结合可抑制肝癌细胞固有性PD-1诱导的肝细胞癌生长

作为单一药物给予的程序性细胞死亡抑制剂1（PD-1）已导致晚期癌症患者的持久性肿瘤消退。但是，只有少数癌症患者对抗PD-1免疫疗法有反应。在这里，我们显示肝细胞癌中PD-1的表达独立于适应性免疫促进肿瘤生长。PD-1的抑制可抑制肿瘤的生长，而PD-1的过表达可增强免疫缺陷异种移植小鼠的肿瘤发生。从机制上讲，PD-1结合雷帕霉素效应子的真核生物起始因子4E和核糖体蛋白S6的下游哺乳动物靶标，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，比单独使用任何一种单独治疗剂都能产生更持久，更协同的肿瘤消退，结论：雷帕霉素途径与PD-1联合靶向哺乳动物可能会提高癌症患者的抗肿瘤功效。（《肝病学》 2017年； 66：1920– 1933年）