Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity

Yazhong Cui, Yang Miao, Longzhi Cao, Lifang Guo, Yue Cui, Chuanzhe Yan, Zhi Zeng, Mo Xu () and Ting Han ()
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Yazhong Cui: Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences
Yang Miao: National Institute of Biological Sciences
Longzhi Cao: Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences
Lifang Guo: Capital Medical University
Yue Cui: National Institute of Biological Sciences
Chuanzhe Yan: National Institute of Biological Sciences
Zhi Zeng: Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences
Mo Xu: Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences
Ting Han: Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Inhibition of T cell infiltration dampens antitumor immunity and causes resistance to immune checkpoint blockade (ICB) therapy. By in vivo CRISPR screening in B16F10 melanoma in female mice, here we report that loss of melanocortin-1 receptor (MC1R) in melanoma cells activates antitumor T cell response and overcomes resistance to ICB. Depletion of MC1R from another melanocytic melanoma model HCmel1274 also enhances ICB efficacy. By activating the GNAS-PKA axis, MC1R inhibits interferon-gamma induced CXCL9/10/11 transcription, thus impairing T cell infiltration into the tumor microenvironment. In human melanomas, high MC1R expression correlates with reduced CXCL9/10/11 expression, impaired T cell infiltration, and poor patient prognosis. Whereas MC1R activation is restricted to melanoma, GNAS activation by hotspot mutations is observed across diverse cancer types and is associated with reduced CXCL9/10/11 expression. Our study implicates MC1R as a melanoma immunotherapy target and suggests GNAS-PKA signaling as a pan-cancer oncogenic pathway inhibiting antitumor T cell response.

Date: 2023
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DOI: 10.1038/s41467-023-41101-3

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