title: 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.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Kleffel
authors.affiliation: 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.
authors.forename: Christian
authors.initials: C
authors.lastname: Posch
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Barthel
authors.affiliation: 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.
authors.forename: Hansgeorg
authors.initials: H
authors.lastname: Mueller
authors.affiliation: Department of Dermatology, University of Bern, 3010 Bern, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schlapbach
authors.affiliation: Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Emmanuella
authors.initials: E
authors.lastname: Guenova
authors.affiliation: 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.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Elco
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Vikram R
authors.initials: VR
authors.lastname: Juneja
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Christine G
authors.initials: CG
authors.lastname: Lian
authors.affiliation: Department of Dermatology, University of Bern, 3010 Bern, Switzerland.
authors.forename: Rahel
authors.initials: R
authors.lastname: Thomi
authors.affiliation: Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Hoetzenecker
authors.affiliation: Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cozzio
authors.affiliation: Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Mihm
authors.affiliation: Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: 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.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Frank
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.affiliation: 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.
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kupper
authors.affiliation: 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.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schatton
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D060890:B7-H1 Antigen / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor
keywords: Melanoma; PD-1; PD-L1; S6 ribosomal protein; antibody; blockade; immune checkpoint; mTOR signaling; p-S6; programmed cell death-1; therapy