Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity
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 c...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41101-3 |
| _version_ | 1797558268242952192 |
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| author | Yazhong Cui Yang Miao Longzhi Cao Lifang Guo Yue Cui Chuanzhe Yan Zhi Zeng Mo Xu Ting Han |
| author_facet | Yazhong Cui Yang Miao Longzhi Cao Lifang Guo Yue Cui Chuanzhe Yan Zhi Zeng Mo Xu Ting Han |
| author_sort | Yazhong Cui |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:27:50Z |
| format | Article |
| id | doaj.art-defb0ce98e1840d69aed0a2851035234 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:27:50Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-defb0ce98e1840d69aed0a28510352342023-11-20T10:07:30ZengNature PortfolioNature Communications2041-17232023-09-0114111810.1038/s41467-023-41101-3Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunityYazhong Cui0Yang Miao1Longzhi Cao2Lifang Guo3Yue Cui4Chuanzhe Yan5Zhi Zeng6Mo Xu7Ting Han8Graduate School of Peking Union Medical College and Chinese Academy of Medical SciencesNational Institute of Biological SciencesGraduate School of Peking Union Medical College and Chinese Academy of Medical SciencesDepartment of Thoracic Surgery, Beijing Chaoyang Hospital, Capital Medical UniversityNational Institute of Biological SciencesNational Institute of Biological SciencesGraduate School of Peking Union Medical College and Chinese Academy of Medical SciencesGraduate School of Peking Union Medical College and Chinese Academy of Medical SciencesGraduate School of Peking Union Medical College and Chinese Academy of Medical SciencesAbstract 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.https://doi.org/10.1038/s41467-023-41101-3 |
| spellingShingle | Yazhong Cui Yang Miao Longzhi Cao Lifang Guo Yue Cui Chuanzhe Yan Zhi Zeng Mo Xu Ting Han Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity Nature Communications |
| title | Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity |
| title_full | Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity |
| title_fullStr | Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity |
| title_full_unstemmed | Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity |
| title_short | Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity |
| title_sort | activation of melanocortin 1 receptor signaling in melanoma cells impairs t cell infiltration to dampen antitumor immunity |
| url | https://doi.org/10.1038/s41467-023-41101-3 |
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