HDAC Inhibitor LBH589 Suppresses the Proliferation but Enhances the Antileukemic Effect of Human γδT Cells.
HDAC Inhibitor LBH589 Suppresses the Proliferation but Enhances the Antileukemic Effect of Human γδT Cells.
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HDAC 抑制剂 LBH589 抑制人 γT 细胞增殖但增强抗白血病作用
DOI：
10.1016/j.omto.2020.08.003
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发表时间：
2020-09-25
期刊：
影响因子：
--
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
He Y;Xu L;Feng J;Wu K;Zhao Y;Huang H
γδT细胞对血液系统恶性肿瘤具有强大的作用，并且其功能可以通过抗肿瘤药物进行调节。组蛋白去乙酰化酶抑制剂（HDACis）不仅具有抗白血病活性，而且在治疗应用过程中会影响免疫细胞。在该体外研究中，我们表明LBH 589（一种泛HDACi）损害人γδT细胞的增殖以及它们在外周血单核细胞（PBMC）中的比例。在特定浓度下，LBH 589诱导γδT细胞对HL-60细胞和Kasumi细胞的抗白血病活性，并呈剂量依赖性。然而，活化受体和分子的表达水平以及γδT细胞上的干扰素-γ（IFN-γ）表达不受LBH 589影响。在用LBH 589处理指定时间后，γδT细胞中的细胞外调节蛋白激酶（ERK）、Akt和c-Jun N-末端激酶（JNK）信号通路未被激活。相反，观察到更强的Notch表达并持续72 h。通过γ-分泌酶抑制剂FLI-06抑制Notch信号传导，显著逆转了由LBH 589诱导的γδT细胞的增强的抗白血病能力。我们的研究首次证明LBH 589可以抑制γδT细胞的增殖，但通过激活Notch信号通路促进其抗白血病作用。γδT细胞对血液系统恶性肿瘤具有有效作用，并且可以通过抗肿瘤剂进行调节。Huang等人结果显示，泛HDAC抑制剂LBH 589通过激活Notch信号通路，抑制人γδT细胞的增殖，但诱导γδT细胞对AML细胞系的显著抗白血病活性。
γδT cells have potent effects on hematological malignancies, and their functions can be regulated by anti-tumor agents. Histone deacetylase inhibitors (HDACis) not only have antileukemic activity on leukemia but also affect immune cells during therapeutic application. In this in vitro study, we showed that LBH589, a pan-HDACi, impaired the proliferation of human γδT cells, as well as their proportions in peripheral blood mononuclear cells (PBMCs). At the specific concentration, LBH589 induced significant antileukemic activity of γδT cells against the HL-60 cells and Kasumi cells in a dose-dependent manner. However, the expression levels of activating receptor and molecules, as well as interferon-γ (IFN-γ) expression on γδT cells, were not affected by LBH589. After treatment with LBH589 for indicated times, extracellular-regulated protein kinase (ERK), Akt, and c-Jun N-terminal kinase (JNK) signaling pathways in γδT cells were not activated. In contrast, a stronger expression of Notch was observed and sustained for 72 h. Inhibition of Notch signaling by FLI-06, the γ-secretase inhibitor, significantly reversed the enhanced antileukemic ability of γδT cells induced by LBH589. For the first time, our investigations demonstrate that LBH589 can inhibit proliferation of γδT cells but facilitate their antileukemic effects via activation of Notch signaling. γδT cells have potent effects on hematological malignancies and can be regulated by anti-tumor agents. Huang et al. showed that pan-HDAC inhibitor, LBH589, impaired the proliferation of human γδT cells but induced significant antileukemic activity of γδT cells against the AML cell lines via activation of Notch signaling.
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