Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth

By S. Kleffel, C. Posch, S. Barthel, Hansgeorg Mueller, C. Schlapbach, Emmanuella Guenova, C. Elco, Nayoung Lee, Vikram R. Juneja, Q. Zhan and 12 more. Cell, 2015

616 citations recorded by the source corpus.

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 RNA interference, 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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/20c9a70172606e266ee642a737538909d81e3d70

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Citations in the corpus

Metabolic Instruction of Immunity (2017, positive): “On this note, tumor cell-intrinsic PD-1 expression may counterintuitively increase intrinsic mTOR signaling and tumor growth (Kleffel et al., 2015).”
Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “Additionally, PD-L1 expressed in melanoma also promotes tumor growth through paracrine or autocrine interaction with PD-1 [134].”
Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade (2018, positive): “These results demonstrate that in models where α PD-1 monotherapy has limited effect (B16) 38 , or where there is some susceptibility to monotherapy (3LL) 39 , DIO mice displayed significantly greater therapeutic efficacy than control recipients.”
Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer (2017, background): “Moreover, it is unclear what the consequences of a mutation in PDCD1, presumably on tumor cells, would be given that PD-1 is expected to function in T-cells although tumor cell autonomous functions have been reported (44).”
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. (2019, background): “In addition, blockade of the PD-1 pathway results in an increase in glucose in the tumor microenvironment that also likely contributes to improved TIL function and tumor regression (116).”
PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity (2017, neutral): “F10 tumors (Chen et al., 2015; Kleffel et al., 2015).”