PD-1 Checkpoint Blockade in Combination with an mTOR Inhibitor Restrains Hepatocellular Carcinoma Growth Induced by Hepatoma Cell-Intrinsic PD-1

ABSTRACT

Inhibitors of 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 (HCC) promotes tumor growth independently of adaptive immunity. Knockdown of PD-1 suppress tumor growth, whereas PD-1 overexpression enhances tumorigenesis in immunodeficient xenografted mice. Mechanistically, PD-1 binds the downstream mTOR effectors eukaryotic initiation factor 4E (eIF4E) and ribosomal protein S6 (S6), thus promoting their phosphorylation. Moreover, combining mTOR 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. Therefore, targeting mTOR pathways in combination with PD-1 may result in increased antitumor efficacy in cancer patients. This article is protected by copyright. All rights reserved.

http://ift.tt/2tNYW59