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

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.