Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth
Authors/Creators
S. Kleffel
C. Posch
S.R. Barthel
H. Mueller
C. Schlapbach
E. Guenova
C.P. Elco
N. Lee
V.R. Juneja
Q. Zhan
C.G. Lian
R. Thomi
W. Hoetzenecker
A. Cozzio
R. Dummer
M.C. Mihm Jr
Kieth T. Flaherty, Edith Cowan University, Australia
G.F. Murphy
A.H. Sharpe
T.S. Kupper
T. Schatton
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.
Keywords
antibody, blockade, immune checkpoint, Melanoma, mTOR signaling, p-S6, PD-1, PD-L1, programmed cell death-1, S6 ribosomal protein, therapy, interleukin 2 receptor, programmed death 1 receptor, adaptive immunity, animal cell, animal tissue, Article, cancer graft, cancer growth, cancer survival, carcinogenesis, carcinogenicity, controlled study, human, human cell, human tissue, immunoblotting, immunofluorescence, immunoreceptor tyrosine based inhibition motif, in vitro study, melanoma, melanoma B16, melanoma cell line, mouse, mutagenesis, nonhuman, overall survival, point mutation, priority journal, progression free survival, protein expression, protein function, protein interaction, protein phosphorylation, reverse transcription polymerase chain reaction, scanning electron microscopy, signal transduction, tumor biopsy, tumor xenograft, upregulation
Document Type
Journal Article
Date of Publication
2015
Publisher
Cell Press
School
School of Medical and Health Sciences
RAS ID
19853
Copyright
free_to_read
Comments
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.