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

Hepatology. 2017 Dec;66(6):1920-1933. doi: 10.1002/hep.29360.


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).

MeSH terms

  • Animals
  • Benzoxazoles / pharmacology
  • Benzoxazoles / therapeutic use*
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Line, Tumor
  • Eukaryotic Initiation Factor-4E / metabolism*
  • Humans
  • Liver Neoplasms, Experimental / drug therapy
  • Liver Neoplasms, Experimental / metabolism*
  • Mice
  • Programmed Cell Death 1 Receptor / metabolism*
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Ribosomal Protein S6 / metabolism*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Xenograft Model Antitumor Assays


  • Benzoxazoles
  • Eukaryotic Initiation Factor-4E
  • Programmed Cell Death 1 Receptor
  • Pyrimidines
  • Ribosomal Protein S6
  • MTOR protein, human
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases
  • sapanisertib