He Ying, Xu Lin, Feng Jingjing, Wu Kangni, Zhao Yanmin, Huang He
Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China.
Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou, Zhejiang 310014, China.
Mol Ther Oncolytics. 2020 Aug 8;18:623-630. doi: 10.1016/j.omto.2020.08.003. eCollection 2020 Sep 25.
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 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细胞对血液系统恶性肿瘤具有强大作用，其功能可由抗肿瘤药物调节。组蛋白去乙酰化酶抑制剂（HDACis）不仅对白血病具有抗白血病活性，而且在治疗应用过程中会影响免疫细胞。在本研究中，我们发现泛HDACi LBH589会损害人γδT细胞的增殖及其在外周血单核细胞（PBMCs）中的比例。在特定浓度下，LBH589以剂量依赖方式诱导γδT细胞对HL-60细胞和Kasumi细胞产生显著的抗白血病活性。然而，γδT细胞上激活受体和分子的表达水平以及干扰素-γ（IFN-γ）的表达不受LBH589影响。用LBH589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氨基末端激酶（JNK）信号通路未被激活。相反，观察到Notch表达增强并持续72小时。γ-分泌酶抑制剂FLI-06抑制Notch信号通路可显著逆转LBH589诱导的γδT细胞增强的抗白血病能力。我们的研究首次证明，LBH589可抑制γδT细胞增殖，但通过激活Notch信号通路促进其抗白血病作用。
