2. Academic Validation
  3. Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity

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

  • Nat Commun. 2023 Sep 15;14(1):5740. doi: 10.1038/s41467-023-41101-3.
Yazhong Cui # 1 2,  Yang Miao # 2 3,  Longzhi Cao 1 2,  Lifang Guo 4,  Yue Cui 2 5,  Chuanzhe Yan 2 6,  Zhi Zeng 1 2,  Mo Xu 7 8 9,  Ting Han 10 11 12
Affiliations

Affiliations

  • 1 Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, 100730, Beijing, China.
  • 2 National Institute of Biological Sciences, 102206, Beijing, China.
  • 3 PTN Joint Graduate Program, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
  • 4 Department of Thoracic Surgery, Beijing Chaoyang Hospital, Capital Medical University, 100020, Beijing, China.
  • 5 Graduate Program, School of Life Sciences, Beijing Normal University, 100875, Beijing, China.
  • 6 PTN Joint Graduate Program, School of Life Sciences, Peking University, 100871, Beijing, China.
  • 7 Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, 100730, Beijing, China. [email protected].
  • 8 National Institute of Biological Sciences, 102206, Beijing, China. [email protected].
  • 9 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, 102206, Beijing, China. [email protected].
  • 10 Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, 100730, Beijing, China. [email protected].
  • 11 National Institute of Biological Sciences, 102206, Beijing, China. [email protected].
  • 12 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, 102206, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 37714844 DOI: 10.1038/s41467-023-41101-3
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.

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