Hepatocellular carcinoma (HCC) often accompanies with resistance to immunotherapies despite the presence of tumor-infiltrating lymphocytes. Here we report that HDAC6 represses TH 17 cell pathogenicity and antitumor immune response dependent on its deacetylase activity. Adoptive transfer of HDAC6-deficient TH 17 cell impedes HCC growth dependent on elevated IL-17A via enhancing the production of antitumor cytokine and CD8+ T cell-mediated antitumor responses. Intriguingly, HDAC6-depleted T cells triggers PD-1-PD-L1 expression to achieve a strong synergistic effect to sensitize advanced HCC to immune checkpoint blocker, while blockade of IL-17A partially suppresses it. Mechanistically, HDAC6 limits TH 17 pathogenicity and antitumor effect through regulating FoxO1. HDAC6 binds and deacetylates cytosolic FoxO1 at K242, which is required for its nuclear translocation and stabilization to repress RoRγt, the transcription factor of TH 17 cell. This regulation of HDAC6 for murine and human TH 17 cell is highly conserved. CONCLUSION: These results demonstrate targeting cytosolic HDAC6-FoxO1 axis reprograms the pathogenicity and antitumor response of TH 17 cells in HCC, with a pathogenicity-driven responsiveness to facilitate immunotherapies.

中文翻译：

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靶向 HDAC6 重编程 TH 17 致病性并促进肝细胞癌的免疫治疗

尽管存在肿瘤浸润淋巴细胞，肝细胞癌 (HCC) 通常伴随着对免疫疗法的抵抗。在这里我们报告 HDAC6 抑制依赖于其脱乙酰酶活性的 TH 17 细胞致病性和抗肿瘤免疫反应。HDAC6 缺陷型 TH 17 细胞的过继转移通过增强抗肿瘤细胞因子的产生和 CD8+ T 细胞介导的抗肿瘤反应，阻碍了依赖于升高的 IL-17A 的 HCC 生长。有趣的是，HDAC6 耗尽的 T 细胞触发 PD-1-PD-L1 表达以实现强大的协同作用，使晚期 HCC 对免疫检查点阻滞剂敏感，而对 IL-17A 的阻断则部分抑制了它。从机制上讲，HDAC6 通过调节 FoxO1 来限制 TH 17 的致病性和抗肿瘤作用。HDAC6 在 K242 处结合并去乙酰化胞质 FoxO1，这是其核易位和稳定化以抑制 TH 17 细胞的转录因子 RoRγt 所必需的。HDAC6 对鼠和人 TH 17 细胞的这种调节是高度保守的。结论：这些结果表明靶向细胞溶质 HDAC6-FoxO1 轴重编程 HCC 中 TH 17 细胞的致病性和抗肿瘤反应，具有促进免疫治疗的致病性驱动的反应性。