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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PD-1 检查点阻断联合 mTOR 抑制剂抑制肝癌细胞内在 PD-1 诱导的肝癌生长

作为单一药物使用的程序性细胞死亡抑制剂 1 (PD-1) 已导致晚期癌症患者的肿瘤持久消退。然而，只有少数癌症患者对抗 PD-1 免疫疗法有反应。在这里，我们表明肝细胞癌中的 PD-1 表达独立于适应性免疫促进肿瘤生长。PD-1 的敲低抑制了肿瘤的生长，而 PD-1 的过表达增强了免疫缺陷异种移植小鼠的肿瘤发生。从机制上讲，PD-1 结合下游哺乳动物靶标的雷帕霉素效应物真核起始因子 4E 和核糖体蛋白 S6，从而促进它们的磷酸化。此外，将哺乳动物雷帕霉素抑制靶点与抗 PD-1 抗体治疗相结合，与单独使用任何一种药物相比，可实现更持久和协同的肿瘤消退，每一种都只表现出适度的功效。结论：靶向雷帕霉素通路的哺乳动物靶点联合 PD-1 可能会提高癌症患者的抗肿瘤疗效。（肝病学 2017；66:1920–1933）