Cell
Volume 162, Issue 6, 10 September 2015, Pages 1242-1256
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Article
Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth

https://doi.org/10.1016/j.cell.2015.08.052Get rights and content
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Highlights

  • Human melanomas frequently contain PD-1-expressing cancer cell subpopulations

  • Inhibition of melanoma-PD-1 reduces tumor growth, independently of adaptive immunity

  • PD-1 overexpression and melanoma-PD-1:PD-L1 interactions promote tumor growth

  • Activation of the melanoma-PD-1 receptor modulates downstream mTOR signaling

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

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

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