Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth
2015
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. | Kupper, Thomas S. | Schatton, Tobias
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.
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