Nature Communications ( IF 14.7 ) Pub Date : 2023-12-09 , DOI: 10.1038/s41467-023-43988-4 Xuemei Gu 1 , Haoran Wei 2 , Caixia Suo 3 , Shengqi Shen 4 , Chuxu Zhu 1 , Liang Chen 1 , Kai Yan 4 , Zhikun Li 1 , Zhenhua Bian 1 , Pinggen Zhang 5 , Mengqiu Yuan 5 , Yingxuan Yu 1 , Jinzhi Du 1 , Huafeng Zhang 5, 6 , Linchong Sun 2 , Ping Gao 1, 2
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.
中文翻译:
衣康酸通过表观遗传诱导 CD8+ T 细胞耗竭促进肝细胞癌进展
衣康酸是一种众所周知的免疫调节代谢物;然而,其在肝细胞癌(HCC)中的作用仍不清楚。在这里,我们发现巨噬细胞衍生的衣康酸通过表观遗传诱导 EOMES 介导的 CD8 + T 细胞耗竭而促进 HCC。我们的结果表明,敲除负责衣康酸生成的免疫反应基因 1 (IRG1) 可抑制 HCC 进展。 Irg1敲除导致 PD-1 +和 TIM-3 + CD8 + T 细胞比例下降。 CD8 + T细胞的缺失或过继转移表明IRG1促进的肿瘤发生依赖于CD8 + T细胞的耗竭。从机制上讲,衣康酸通过促进Eomes启动子的琥珀酸依赖性 H3K4me3 上调 PD-1 和 TIM-3 表达水平。最后,发现布洛芬通过靶向 IRG1/衣康酸依赖性肿瘤免疫逃避来抑制 HCC 进展,巨噬细胞中IRG1 的高表达预示着 HCC 患者预后不良。综上所述,我们的结果揭示了衣康酸和 HCC 之间的表观遗传联系,并表明靶向 IRG1 或衣康酸可能是 HCC 治疗的一种有前途的策略。