Title

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

Document Type

Journal Article

Publisher

Cell Press

School

School of Medical and Health Sciences

RAS ID

19853

Comments

Originally published as: Kleffel, S., Posch, C., Barthel, et al. (2015). Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth in Cell, 162(6), 1242-1256. Available here.

Abstract

Summary 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.

DOI

10.1016/j.cell.2015.08.052

Access Rights

Free to read at publisher's website