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

Details

Serval ID
serval:BIB_EFA7514C3942
Type
Article: article from journal or magazin.
Collection
Publications
Title
Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth.
Journal
Cell
Author(s)
Kleffel S., Posch C., Barthel S.R., Mueller H., Schlapbach C., Guenova E., Elco C.P., Lee N., Juneja V.R., Zhan Q., Lian C.G., Thomi R., Hoetzenecker W., Cozzio A., Dummer R., Mihm M.C., Flaherty K.T., Frank M.H., Murphy G.F., Sharpe A.H., Kupper T.S., Schatton T.
ISSN
1097-4172 (Electronic)
ISSN-L
0092-8674
Publication state
Published
Issued date
10/09/2015
Peer-reviewed
Oui
Volume
162
Number
6
Pages
1242-1256
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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
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, Melanoma, PD-1, PD-L1, S6 ribosomal protein, antibody, blockade, immune checkpoint, mTOR signaling, p-S6, programmed cell death-1, therapy
Pubmed
Web of science
Open Access
Yes
Create date
27/08/2020 14:59
Last modification date
02/09/2020 6:26
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