Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor Cells
Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor Cells
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DOI：
10.3389/fimmu.2019.00569
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发表时间：
2019-03-27
影响因子：
7.3
通讯作者：
Kabelitz, Dieter
中科院分区：
文献类型：
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作者：
Bhat, Jaydeep;Dubin, Samuel;Kabelitz, Dieter
人γ δ T细胞的功能可塑性和抗肿瘤潜力已被广泛研究。然而，γ δ T细胞/肿瘤细胞相互作用的表观遗传调控研究甚少。在本研究中，我们发现，组蛋白去乙酰化酶抑制剂丙戊酸（VPA）治疗显著增强胰腺癌细胞系Panc 89和前列腺癌细胞系PC-3中NKG 2D配体云母、MICB和ULBP-2的表达和/或释放，但不增强ULBP-1。在体外肿瘤共培养条件下，γ δ T细胞中全长和截短形式的NKG 2D受体表达显著下调。此外，使用新建立的基于流式细胞术的方法来分析γ δ T细胞中的组蛋白乙酰化（H3 K9 ac），我们在V δ 2 T细胞中显示了组成型H3 K9 ac（低）和诱导型H3 K9 ac（高）表达。H3 K9 ac（低）V δ 2 T细胞的详细分析揭示了在与胰腺导管腺癌细胞体外共培养期间T-EMRA向T-EM表型的显著逆转。我们的研究揭示了表观遗传修饰剂如何在与肿瘤细胞相互作用期间调节γ δ T细胞分化的新机制。当考虑VPA与基于γ δ T细胞的免疫疗法联合治疗某些类型的癌症时，这一信息很重要。
The functional plasticity and anti-tumor potential of human gamma delta T cells have been widely studied. However, the epigenetic regulation of gamma delta T-cell/tumor cell interactions has been poorly investigated. In the present study, we show that treatment with the histone deacetylase inhibitor Valproic acid (VPA) significantly enhanced the expression and/or release of the NKG2D ligands MICA, MICB and ULBP-2, but not ULBP-1 in the pancreatic carcinoma cell line Panc89 and the prostate carcinoma cell line PC-3. Under in vitro tumor co-culture conditions, the expression of full length and the truncated form of the NKG2D receptor in gamma delta T cells was significantly downregulated. Furthermore, using a newly established flow cytometry-based method to analyze histone acetylation (H3K9ac) in gamma delta T cells, we showed constitutive H3K9ac(low) and inducible H3K9ac(high) expression in V delta 2 T cells. The detailed analysis of H3K9ac(low) V delta 2 T cells revealed a significant reversion of T-EMRA to T-EM phenotype during in vitro co-culture with pancreatic ductal adenocarcinoma cells. Our study uncovers novel mechanisms of how epigenetic modifiers modulate gamma delta T-cell differentiation during interaction with tumor cells. This information is important when considering combination therapy of VPA with the gamma delta T-cell-based immunotherapy for the treatment of certain types of cancer.