EZH2 Inhibitor GSK126 Suppresses Antitumor Immunity by Driving Production of Myeloid-Derived Suppressor Cells
EZH2 Inhibitor GSK126 Suppresses Antitumor Immunity by Driving Production of Myeloid-Derived Suppressor Cells
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EZH2 抑制剂 GSK126 通过驱动骨髓源性抑制细胞的产生来抑制抗肿瘤免疫
DOI：
10.1158/0008-5472.can-18-2395
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发表时间：
2019-04-15
期刊：
影响因子：
11.2
通讯作者：
Zhu, Bo
中科院分区：
文献类型：
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作者：
Huang, Shuo;Wang, Zhongyu;Zhu, Bo
zeste同源物增强子（EZH 2）是基因表达的关键表观遗传调节因子，经常在各种癌症类型中过表达，表明在肿瘤发生中的作用。目前正在探索EZH 2抑制剂的治疗潜力，但它们对抗肿瘤免疫的影响在很大程度上是未知的。在这里，我们报告使用EZH 2抑制剂GSK 126抑制EZH 2活性导致髓源性抑制细胞（MDSC）数量增加，CD 4（+）和IFN γ（+）CD 8（+）T细胞减少，这些细胞参与抗肿瘤免疫。添加针对骨髓分化抗原GR-1的中和抗体或吉西他滨/5-氟尿嘧啶耗尽的MDSC减轻了MDSC介导的免疫抑制，并增加了CD 4（+）和CD 8（+）T细胞肿瘤浸润和GSK 126治疗功效。从机制上讲，我们鉴定了癌症中MDSC产生的新途径，其中EZH 2抑制指导原始造血祖细胞的骨髓分化。这些发现表明，调节肿瘤免疫微环境可以提高EZH 2抑制剂的疗效。
Enhancer of zeste homolog (EZH2) is a key epigenetic regulator of gene expression and is frequently overexpressed in various cancer types, suggesting a role in oncogenesis. The therapeutic potential of EZH2 inhibitors is currently being explored, but their effect on antitumor immunity is largely unknown. Here we report that suppressing EZH2 activity using EZH2 inhibitor GSK126 resulted in increased numbers of myeloid-derived suppressor cells (MDSC) and fewer CD4(+) and IFN gamma(+)CD8(+) T cells, which are involved in antitumor immunity. Addition of a neutralizing antibody against the myeloid differentiation antigen GR-1 or gemcitabine/5-fluorouracil-depleted MDSCs alleviated MDSC-mediated immunosuppression and increased CD4(+) and CD8(+) T-cell tumor infiltration and GSK126 therapeutic efficacy. Mechanistically, we identified a novel pathway of MDSC production in cancer in which EZH2 inhibition directs myeloid differentiation from primitive hematopoietic progenitor cells. These findings suggest that modulating the tumor immune microenvironment may improve the efficacy of EZH2 inhibitors.