Checkpoint Blockade Rescues the Repressive Effect of Histone Deacetylases Inhibitors on γδ T Cell Function.
Checkpoint Blockade Rescues the Repressive Effect of Histone Deacetylases Inhibitors on γδ T Cell Function.
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DOI：
10.3389/fimmu.2018.01615
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发表时间：
2018
影响因子：
7.3
通讯作者：
Chiplunkar SV
中科院分区：
文献类型：
--
作者：
Bhat SA;Vedpathak DM;Chiplunkar SV
组蛋白脱乙酰酶(HDAC)是控制染色质可及性和基因表达的关键表观遗传修饰因子之一。它们在肿瘤发生中的作用已经确立，HDAC抑制剂已经成为一种有效的治疗方式。HDAC抑制剂因其独特的抗肿瘤活性而被研究，并在临床上用于各种恶性肿瘤的治疗。在本研究中，我们研究了HDAC抑制剂对人γδT细胞效应器功能的影响。HDAC抑制剂可抑制γδT细胞的抗原特异性增殖反应和细胞周期进程。在抗原激活的γδT细胞中，经HDAC抑制剂处理后，转录因子(eOMES和Tbet)和效应分子(穿孔素和颗粒酶B)的表达减少。经HDAC抑制剂处理后，γδT细胞的抗肿瘤细胞毒作用减弱，这与γδT细胞中免疫检查点程序性死亡-1(PD-1)和程序性死亡配体-1的表达增强有关。有趣的是，PD-1阻断改善了经HDAC抑制剂处理的γδT细胞的抗肿瘤效应功能，这反映在颗粒酶B和LAMP-1的表达增加。本研究为设计HDAC抑制剂和免疫检查点阻断作为癌症的联合治疗方案提供了理论依据。
Histone deacetylases (HDAC) are one of the key epigenetic modifiers that control chromatin accessibility and gene expression. Their role in tumorigenesis is well established and HDAC inhibitors have emerged as an effective treatment modality. HDAC inhibitors have been investigated for their specific antitumor activities and also clinically evaluated in treatment of various malignancies. In the present study, we have investigated the effect of HDAC inhibitors on the effector functions of human γδ T cells. HDAC inhibitors inhibit the antigen-specific proliferative response of γδ T cells and cell cycle progression. In antigen-activated γδ T cells, the expression of transcription factors (Eomes and Tbet) and effector molecules (perforin and granzyme B) were decreased upon treatment with HDAC inhibitors. Treatment with HDAC inhibitors attenuated the antitumor cytotoxic potential of γδ T cells, which correlated with the enhanced expression of immune checkpoints programmed death-1 (PD-1) and programmed death ligand-1 in γδ T cells. Interestingly, PD-1 blockade improves the antitumor effector functions of HDAC inhibitor-treated γδ T cells, which is reflected in the increased expression of Granzyme B and Lamp-1. This study provides a rationale for designing HDAC inhibitor and immune check point blockade as a combinatorial treatment modality for cancer.
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影响因子：
4.4
作者：
Glauben, Rainer;Batra, Arvind;Siegmund, Britta
通讯作者：
Siegmund, Britta
影响因子：
4.4
作者：
Corvaisier, M;Moreau-Aubry, A;Jotereau, F
通讯作者：
Jotereau, F
影响因子：
8
作者：
Borbone, E.;Berlingieri, M. T.;Fusco, A.
通讯作者：
Fusco, A.
DOI：
10.4049/jimmunol.0802598
发表时间：
2009-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Cho OH;Shin HM;Miele L;Golde TE;Fauq A;Minter LM;Osborne BA
通讯作者：
Osborne BA
影响因子：
11.2
作者：
Banerjee A;Thyagarajan K;Chatterjee S;Chakraborty P;Kesarwani P;Soloshchenko M;Al-Hommrani M;Andrijauskaite K;Moxley K;Janakiraman H;Scheffel MJ;Helke K;Armenson K;Palanisamy V;Rubinstein MP;Mayer EG;Cole DJ;Paulos CM;Christina-Voelkel-Johnson;Nishimura MI;Mehrotra S
通讯作者：
Mehrotra S