PO.TB10.17 · 肿瘤生物学
组蛋白去乙酰化酶 9（HDAC9）通过调节肿瘤-中性粒细胞相互作用介导晚期肝细胞癌的治疗抵抗
Histone deacetylase 9 (HDAC9) mediates therapy resistance by regulating tumor-neutrophil interaction in advanced hepatocellular carcinoma
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摘要 Abstract
中文摘要
酪氨酸激酶抑制剂（TKIs）和免疫检查点阻断（ICB）疗法是晚期肝细胞癌（HCC）的标准治疗，但其疗效受治疗抵抗的限制。本研究探讨了抵抗的潜在机制，聚焦于肿瘤-免疫相互作用的作用。在 TKI 治疗的免疫健全小鼠模型中使用单细胞 RNA 测序（scRNA-seq），我们鉴定出低分化肿瘤细胞的扩增，伴随组蛋白去乙酰化酶 9（HDAC9）的显著上调。HDAC9 升高增强了癌症干性并降低了 TKI 治疗的疗效。除 TKIs 外，HDAC9 还通过抑制 CD8+ T 细胞浸润和细胞毒性促进 ICB 抵抗，部分是通过与呈现中性粒细胞胞外诱捕网（NET）表型的免疫抑制性中性粒细胞相互作用。中性粒细胞清除逆转了 ICB 抵抗，恢复了 CD8+ T 细胞的浸润和功能。机制上，HDAC9 使翻译起始因子 4 gamma 2（eIF4G2）去乙酰化，增强其与 YTHDF3 的相互作用以促进 m6A 依赖性蛋白翻译，包括介导肿瘤-中性粒细胞串扰的信号分子。临床病理分析证实，在 HCC 患者中 HDAC9 与中性粒细胞浸润增加及细胞毒性免疫活性降低相关。这些发现将 HDAC9 确定为驱动治疗抵抗的关键免疫调节因子，并提示靶向 HDAC9/eIF4G2/YTHDF3 轴可能改善 TKI 和 ICB 疗法在晚期 HCC 中的疗效。
查看英文原文 English abstract
Tyrosine kinase inhibitors (TKIs) and immune checkpoint blockade (ICB) therapies are standard treatments for advanced hepatocellular carcinoma (HCC), but their efficacy is limited by therapy resistance. This study investigates the mechanisms underlying resistance, focusing on the role of tumor-immune interaction. Using single-cell RNA sequencing (scRNA-seq) in a TKI-treated immunocompetent mouse model, we identified an expansion of poorly differentiated tumor cells with significant upregulation of histone deacetylase 9 (HDAC9). Elevated HDAC9 enhanced cancer stemness and reduced the efficacy of TKI therapy. Beyond TKIs, HDAC9 also contributed to ICB resistance by suppressing CD8 + T cell infiltration and cytotoxicity, partly through interactions with immunosuppressive neutrophils exhibiting a neutrophil extracellular trap (NET) phenotype. Neutrophil depletion reversed ICB resistance, restoring CD8 + T cell infiltration and function. Mechanistically, HDAC9 deacetylates translation initiation factor 4 gamma 2 (eIF4G2), enhancing its interaction with YTHDF3 to promote m6A-dependent protein translation, including signaling molecules that mediate tumor-neutrophil crosstalk. Clinicopathological analysis confirmed that HDAC9 correlates with increased neutrophil infiltration and reduced cytotoxic immune activity in HCC patients. These findings identify HDAC9 as a key immunoregulator driving therapy resistance and suggest that targeting the HDAC9/eIF4G2/YTHDF3 axis may improve the efficacy of TKI and ICB therapies in advanced HCC.
利益披露 Disclosure
Y. Xie, None..
M. Zhang, None..
L. Liu, None..
Y. He, None..
J. Cai, None..
C. Chung, None..
L. Hoi Wing, None..
S. Ma, None..
K. To, None..
J. Zhou, None..
C. C. Tong, None.