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

Kleffel, Sonja; Posch, Christian; Barthel, Steven R; Mueller, Hansgeorg; Schlapbach, Christoph; Guenova, Emmanuella; Elco, Christopher P; Lee, Nayoung; Juneja, Vikram R; Zhan, Qian; Lian, Christine G; Thomi, Rahel; Hoetzenecker, Wolfram; Cozzio, Antonio; Dummer, Reinhard; Mihm, Martin C; Flaherty, Keith T; Frank, Markus H; Murphy, George F; Sharpe, Arlene H; ... (2015). Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. Cell, 162(6), pp. 1242-1256. Cell Press 10.1016/j.cell.2015.08.052

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Dermatology

UniBE Contributor:

Schlapbach, Christoph

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0092-8674

Publisher:

Cell Press

Language:

English

Submitter:

Sandra Nyffenegger

Date Deposited:

09 Mar 2016 14:42

Last Modified:

15 Feb 2017 14:19

Publisher DOI:

10.1016/j.cell.2015.08.052

PubMed ID:

26359984

Uncontrolled Keywords:

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

BORIS DOI:

10.7892/boris.76570

URI:

https://boris.unibe.ch/id/eprint/76570

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