Xie Zhiqi, Shao Jinjin, Shen Zeren, Ye Zhichao, Okada Yoshiaki, Okuzaki Daisuke, Okada Naoki, Tachibana Masashi
Wuyi First People's Hospital, Affiliated Hospital, School of Medicine, Hangzhou City University, Hangzhou, 310015, China.
Project for Vaccine and Immune Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0871, Japan.
Cancer Immunol Immunother. 2025 Feb 1;74(3):81. doi: 10.1007/s00262-024-03931-y.
Myeloid-derived suppressor cells (MDSCs) play a critical role in cancer progression and resistance, thus representing promising targets for immunotherapy. Despite the established role of histone deacetylases (HDACs) in epigenetic regulation of cell fate and function, their specific impact on MDSCs remains elusive. We sought to investigate the effects and underlying mechanisms of HDAC on MDSCs using various HDAC inhibitors. Our results indicate that HDAC1-3 inhibitors reduce CCR2 expression, a chemokine receptor that mediates the migration of monocytic (M-)MDSCs to tumors and attenuated the immunosuppressive activity of MDSCs. In an orthotropic hepatocellular carcinoma (HCC) murine model, HDAC1-3 inhibitors reduced the infiltration of M-MDSCs, increased the number of natural killer cells in tumors, and suppressed tumor growth. Our results also suggest that HDAC1-3 inhibitors potentiate the antitumor effects of anti-programmed cell death protein 1 antibodies. ATAC-seq and RNA-seq analyses revealed 115 genes epigenetically upregulated by HDAC1-3 inhibitors, primarily linked to transcriptional regulation and ubiquitination. We further elucidated that HDAC1-3 inhibitors facilitate CCR2 protein degradation through ubiquitination-mediated by NEDD4 E3 ligase. Our findings reveal a novel mechanism of action of HDAC1-3 inhibitors in MDSCs and suggest a potential synergistic immunotherapy strategy for clinical benefit in HCC.
髓源性抑制细胞（MDSCs）在癌症进展和耐药中起关键作用，因此是免疫治疗的有前景的靶点。尽管组蛋白去乙酰化酶（HDACs）在细胞命运和功能的表观遗传调控中已确立作用，但其对MDSCs的具体影响仍不清楚。我们试图使用各种HDAC抑制剂研究HDAC对MDSCs的影响及其潜在机制。我们的结果表明，HDAC1 - 3抑制剂降低CCR2表达，CCR2是一种趋化因子受体，介导单核细胞（M -）MDSCs向肿瘤的迁移，并减弱MDSCs的免疫抑制活性。在原位肝细胞癌（HCC）小鼠模型中，HDAC1 - 3抑制剂减少M - MDSCs的浸润，增加肿瘤中自然杀伤细胞的数量，并抑制肿瘤生长。我们的结果还表明，HDAC1 - 3抑制剂增强抗程序性细胞死亡蛋白1抗体的抗肿瘤作用。ATAC - seq和RNA - seq分析揭示了115个基因被HDAC1 - 3抑制剂表观遗传上调，主要与转录调控和泛素化有关。我们进一步阐明，HDAC1 - 3抑制剂通过NEDD4 E3连接酶介导的泛素化促进CCR2蛋白降解。我们的发现揭示了HDAC1 - 3抑制剂在MDSCs中的一种新作用机制，并为HCC临床获益提出了一种潜在的协同免疫治疗策略。
