Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth.

Abstract

Therapeutic antibodies targeting programmed cell death 1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here, we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNAi, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised, and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy.

• Authors: Sonja Kleffel, Christian Posch, Steven R Barthel, Hansgeorg Mueller, Christoph Schlapbach, Emmanuella Guenova, Christopher P Elco, Nayoung Lee, Vikram R Juneja, Qian Zhan, Christine G Lian, Rahel Thomi, Wolfram Hoetzenecker, Antonio Cozzio, Reinhard Dummer, Martin C Mihm Jr, Keith T Flaherty, Markus H Frank, George F Murphy, Arlene H Sharpe, Thomas S Kupper, Tobias Schatton
• Journal: Cell (Cell) Vol. 162 Issue 6 Pg. 1242-56 (Sep 10 2015) ISSN: 1097-4172 [Electronic] United States
• PMID: 26359984 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• B7-H1 Antigen
• PDCD1 protein, human
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor

Topics

• Animals
• Antineoplastic Agents (administration & dosage)
• B7-H1 Antigen (genetics)
• Cell Line, Tumor
• Cells, Cultured
• Gene Knockdown Techniques
• Heterografts
• Humans
• Melanoma (genetics)
• Mice
• Mice, Inbred C57BL
• Neoplasm Transplantation
• Programmed Cell Death 1 Receptor (metabolism)
• Signal Transduction