期刊
CELL
卷 162, 期 6, 页码 1242-1256出版社
CELL PRESS
DOI: 10.1016/j.cell.2015.08.052
关键词
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资金
- Melanoma International Foundation
- Brigham Research Institute
- Brigham and Women's Hospital, Department of Dermatology
- Swiss National Science Foundation [PMDPP3_151326]
- NIH/NCI [1R01CA158467, U54 CA163125]
- Dermatology Foundation
- Austrian Society of Dermatology and Venereology
- Fondation Rene Touraine
- Outrun the Sun Melanoma Foundation
- American Skin Association
- Department of Defense through the National Defense Science and Engineering Graduate Fellowship (NDSEG) Program
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, themelanoma-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.
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