Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8 + T-cell exhaustion.
Autor: | Gu X; School of Medicine, South China University of Technology, Guangzhou, China., Wei H; Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China., Suo C; Department of Colorectal Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China., Shen S; Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China., Zhu C; School of Medicine, South China University of Technology, Guangzhou, China., Chen L; School of Medicine, South China University of Technology, Guangzhou, China., Yan K; Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China., Li Z; School of Medicine, South China University of Technology, Guangzhou, China., Bian Z; School of Medicine, South China University of Technology, Guangzhou, China., Zhang P; The 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 China, Hefei, China., Yuan M; The 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 China, Hefei, China., Yu Y; School of Medicine, South China University of Technology, Guangzhou, China., Du J; School of Medicine, South China University of Technology, Guangzhou, China., Zhang H; The 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 China, Hefei, China. hzhang22@ustc.edu.cn.; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China. hzhang22@ustc.edu.cn., Sun L; Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China. sunlc@mail.ustc.edu.cn., Gao P; School of Medicine, South China University of Technology, Guangzhou, China. pgao2@ustc.edu.cn.; Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China. pgao2@ustc.edu.cn. |
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Jazyk: | angličtina |
Zdroj: | Nature communications [Nat Commun] 2023 Dec 09; Vol. 14 (1), pp. 8154. Date of Electronic Publication: 2023 Dec 09. |
DOI: | 10.1038/s41467-023-43988-4 |
Abstrakt: | 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. (© 2023. The Author(s).) |
Databáze: | MEDLINE |
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