Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion
Abstract Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8+ T-cell exhaustion. Our results show that the...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-43988-4 |
| _version_ | 1797397866506878976 |
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| author | Xuemei Gu Haoran Wei Caixia Suo Shengqi Shen Chuxu Zhu Liang Chen Kai Yan Zhikun Li Zhenhua Bian Pinggen Zhang Mengqiu Yuan Yingxuan Yu Jinzhi Du Huafeng Zhang Linchong Sun Ping Gao |
| author_facet | Xuemei Gu Haoran Wei Caixia Suo Shengqi Shen Chuxu Zhu Liang Chen Kai Yan Zhikun Li Zhenhua Bian Pinggen Zhang Mengqiu Yuan Yingxuan Yu Jinzhi Du Huafeng Zhang Linchong Sun Ping Gao |
| author_sort | Xuemei Gu |
| collection | DOAJ |
| description | Abstract Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8+ T-cell exhaustion. Our results show that the knockout of immune-responsive gene 1 (IRG1), responsible for itaconate production, suppresses HCC progression. Irg1 knockout leads to a decreased proportion of PD-1+ and TIM-3+ CD8+ T cells. Deletion or adoptive transfer of CD8+ T cells shows that IRG1-promoted tumorigenesis depends on CD8+ T-cell exhaustion. Mechanistically, itaconate upregulates PD-1 and TIM-3 expression levels by promoting succinate-dependent H3K4me3 of the Eomes promoter. Finally, ibuprofen is found to inhibit HCC progression by targeting IRG1/itaconate-dependent tumor immunoevasion, and high IRG1 expression in macrophages predicts poor prognosis in HCC patients. Taken together, our results uncover an epigenetic link between itaconate and HCC and suggest that targeting IRG1 or itaconate might be a promising strategy for HCC treatment. |
| first_indexed | 2024-03-09T01:16:25Z |
| format | Article |
| id | doaj.art-4163011c71344526b7413ca7b235ea75 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T01:16:25Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-4163011c71344526b7413ca7b235ea752023-12-10T12:25:26ZengNature PortfolioNature Communications2041-17232023-12-0114111510.1038/s41467-023-43988-4Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustionXuemei Gu0Haoran Wei1Caixia Suo2Shengqi Shen3Chuxu Zhu4Liang Chen5Kai Yan6Zhikun Li7Zhenhua Bian8Pinggen Zhang9Mengqiu Yuan10Yingxuan Yu11Jinzhi Du12Huafeng Zhang13Linchong Sun14Ping Gao15School of Medicine, South China University of TechnologyMedical Research Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityDepartment of Colorectal Surgery, Guangzhou First People’s Hospital, School of Medicine, South China University of TechnologyGuangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical SciencesSchool of Medicine, South China University of TechnologySchool of Medicine, South China University of TechnologyGuangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical SciencesSchool of Medicine, South China University of TechnologySchool of Medicine, South China University of TechnologyThe Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of ChinaThe Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of ChinaSchool of Medicine, South China University of TechnologySchool of Medicine, South China University of TechnologyThe Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of ChinaMedical Research Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversitySchool of Medicine, South China University of TechnologyAbstract Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8+ T-cell exhaustion. Our results show that the knockout of immune-responsive gene 1 (IRG1), responsible for itaconate production, suppresses HCC progression. Irg1 knockout leads to a decreased proportion of PD-1+ and TIM-3+ CD8+ T cells. Deletion or adoptive transfer of CD8+ T cells shows that IRG1-promoted tumorigenesis depends on CD8+ T-cell exhaustion. Mechanistically, itaconate upregulates PD-1 and TIM-3 expression levels by promoting succinate-dependent H3K4me3 of the Eomes promoter. Finally, ibuprofen is found to inhibit HCC progression by targeting IRG1/itaconate-dependent tumor immunoevasion, and high IRG1 expression in macrophages predicts poor prognosis in HCC patients. Taken together, our results uncover an epigenetic link between itaconate and HCC and suggest that targeting IRG1 or itaconate might be a promising strategy for HCC treatment.https://doi.org/10.1038/s41467-023-43988-4 |
| spellingShingle | Xuemei Gu Haoran Wei Caixia Suo Shengqi Shen Chuxu Zhu Liang Chen Kai Yan Zhikun Li Zhenhua Bian Pinggen Zhang Mengqiu Yuan Yingxuan Yu Jinzhi Du Huafeng Zhang Linchong Sun Ping Gao Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion Nature Communications |
| title | Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion |
| title_full | Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion |
| title_fullStr | Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion |
| title_full_unstemmed | Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion |
| title_short | Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion |
| title_sort | itaconate promotes hepatocellular carcinoma progression by epigenetic induction of cd8 t cell exhaustion |
| url | https://doi.org/10.1038/s41467-023-43988-4 |
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