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

S. Kleffel, C. Posch, S. Barthel, H. Mueller, C. Schlapbach, E. Guenova, C. P. Elco, Nayoung Lee, Vikram R. Juneja, Q. Zhan, C. Lian, R. Thomi, W. Hoetzenecker, A. Cozzio, R. Dummer, M. Mihm, K. Flaherty, M. Frank, G. F. Murphy, A. Sharpe, T. Kupper, T. Schatton
Published 2015 · Biology, Medicine

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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.
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