目的:肝脏是生酮的主要器官,而酮主要通过关键酶OXCT1在外周组织中代谢。我们以前发现,在肝细胞癌(HCC)细胞中,酮溶解通过OXCT1表达重新激活以促进肿瘤进展;然而,OXCT1是否调节抗肿瘤免疫仍不清楚.
方法:探讨OXCT1在肝细胞癌中的体内表达规律,我们对人类HCC标本进行了多重免疫组织化学(mIHC)实验。探讨OXCT1在小鼠肝癌肿瘤相关巨噬细胞(TAMs)中的作用,我们产生了LysMcreOXCT1f/f(巨噬细胞中的OXCT1条件性敲除)小鼠。
结果:这里,我们发现,抑制肿瘤相关巨噬细胞中OXCT1的表达通过琥珀酸-H3K4me3-Arg1轴减少CD8+T细胞耗竭.最初,我们发现OXCT1在稳态下在肝巨噬细胞中高表达,而OXCT在TAM中的表达进一步增加。巨噬细胞中的OXCT1缺乏通过将TAM重编程为抗肿瘤表型而抑制肿瘤生长,减少CD8+T细胞耗竭和增加CD8+T细胞的细胞毒性。机械上,高OXCT1表达诱导琥珀酸的积累,酮分解的副产品,在TAM中,它通过增加Arg1启动子中的H3K4三甲基化(H3K4me3)水平来促进Arg1转录。此外,匹莫齐特,OXCT1的抑制剂,抑制Arg1表达以及TAM向原瘤表型的极化,导致CD8+T细胞耗竭减少和肿瘤生长减速。最后,巨噬细胞中OXCT1的高表达与HCC患者的低生存率呈正相关.
结论:结论:我们的结果表明,OXCT1表观遗传抑制抗肿瘤免疫,提示抑制TAMs中的OXCT1活性是治疗肝癌的有效方法。
■肝脏巨噬细胞的复杂代谢在塑造HCC进展和免疫调节中起着关键作用。靶向巨噬细胞代谢以抵消免疫抑制是HCC的有希望的途径。这里,我们发现生酮基因OXCT1在肿瘤相关巨噬细胞中高表达,并通过将TAMs重编程为原瘤表型促进肿瘤生长.TAMs中OXCT1的战略药物干预或基因下调可增强抗肿瘤免疫力,减缓肿瘤生长。我们的结果表明,抑制TAM中的OXCT1活性是治疗肝癌的有效方法。
OBJECTIVE: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear.
METHODS: To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice.
RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8+ T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC.
CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.
UNASSIGNED: The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.