Hepatocellular carcinoma (HCC) is often diagnosed at the unresectable stage with limited treatment options.1 Immunotherapy with immune checkpoint blockade (ICB) has been shown to provide significant survival benefit for HCC patients with advanced disease. Two combination therapies of anti-PD-L1 plus anti-VEGF or anti-PD1 plus anti-CTLA4 represent the current first-line treatments for unresectable HCC.2 3 However, only about one-third of patients respond to therapy, typically in the context of immune-enriched (‘hot’) tumour microenvironments.4 5 Therefore, there is a major need for treatment strategies that overcome ICB resistance. In Gut , Tu et al observe a correlation of poor prognostic outcomes by anti-PD-1-treated patients with high expression of major histone deacetylases (HDACs) by HCC tumours.6 They, therefore, test the potential of epigenetic immunotherapy combining HDAC inhibitors with ICB therapy in preclinical animal models and provide evidence that the epigenetic immunotherapy approach can be effective by enhancing CD8+T cell responses and driving pyroptosis of tumour cells in ICB-resistant HCC.6 Cancers are well recognised to undergo major epigenetic transitions.7 Modification of histones by histone acetylation and deacetylation is a primary epigenetic mechanism that regulates chromatin accessibility, for example, by acetylation of histone H3 at lysine 27 enhancing accessibility and transcriptional output. In contrast, histone deacetylation by HDACs promotes a more compact …

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结合表观遗传调控：HCC 免疫治疗的下一步？


肝细胞癌 （HCC） 通常在不可切除的阶段被诊断出来，治疗选择有限。免疫检查点阻断 （ICB） 的免疫疗法已被证明可为晚期 HCC 患者提供显著的生存获益。抗 PD-L1 加抗 VEGF 或抗 PD1 加抗 CTLA4 的两种联合疗法代表了目前不可切除 HCC 的一线治疗2 3 然而，只有大约三分之一的患者对治疗有反应，通常是在免疫富集（“热”）肿瘤微环境中4 5 因此，迫切需要克服 ICB 耐药性的治疗策略。在 Gut 中，Tu 等人观察到抗 PD-1 治疗患者的不良预后与 HCC 肿瘤高表达主要组蛋白脱乙酰酶 （HDAC） 的相关性6 因此，他们在临床前动物模型中测试了表观遗传免疫疗法将 HDAC 抑制剂与 ICB 疗法相结合的潜力，并提供证据表明表观遗传免疫疗法可以通过增强 CD8+T 细胞反应和驱动 ICB 耐药 HCC 中肿瘤细胞的焦亡来有效。癌症是7 组蛋白乙酰化和去乙酰化对组蛋白的修饰是调节染色质可及性的主要表观遗传机制，例如，通过组蛋白 H3 在赖氨酸 27 位点的乙酰化增强可及性和转录输出。相比之下，HDAC 的组蛋白脱乙酰促进了更紧凑的 ...