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Cell. 2015 Sep 10;162(6):1242-56. doi: 10.1016/j.cell.2015.08.052.

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

Author information

1
Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
2
Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Dermatology, The Rudolfstiftung Hospital, 1030 Vienna, Austria.
3
Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Dermatology, Innsbruck Medical University, 6020 Innsbruck, Austria.
4
Department of Dermatology, University of Bern, 3010 Bern, Switzerland.
5
Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland.
6
Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
7
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
8
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
9
Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
10
Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA; School of Medical Sciences, Edith Cowan University, Joondalup, WA 6027, Australia.
11
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
12
Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA. Electronic address: tschatton@bwh.harvard.edu.

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.

KEYWORDS:

Melanoma; PD-1; PD-L1; S6 ribosomal protein; antibody; blockade; immune checkpoint; mTOR signaling; p-S6; programmed cell death-1; therapy

PMID:
26359984
PMCID:
PMC4700833
DOI:
10.1016/j.cell.2015.08.052
[Indexed for MEDLINE]
Free PMC Article
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