T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8+ T-Cell Exhaustion and Poor Clinical Outcome in AML Patients
T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8+ T-Cell Exhaustion and Poor Clinical Outcome in AML Patients
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T细胞免疫球蛋白及其ITIM结构域(TIGIT)与AML患者CD8+T细胞耗竭和不良临床结局的关系
DOI：
10.1158/1078-0432.ccr-15-2626
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发表时间：
2016-06-15
影响因子：
11.5
通讯作者：
Zheng, Hong
中科院分区：
文献类型：
--
作者：
Kong, Yaxian;Zhu, Liuluan;Zheng, Hong
目的：T细胞免疫球蛋白和免疫受体酪氨酸基抑制基序（ITIM）结构域（TIGIT）是最近鉴定的T细胞共抑制受体。在这项研究中，我们旨在确定TIGIT在急性髓细胞性白血病（AML）患者中的临床影响，并剖析TIGIT在白血病进展的发病机制中的作用。实验设计：通过流式细胞术检查从AML患者收集的外周血T细胞上的TIGIT表达。分析了TIGIT表达与临床结果的相关性，包括AML患者中同种异体干细胞移植（alloSCT）后的完全缓解和复发率。进行表达TIGIT的T细胞的表型和功能研究（细胞因子释放、增殖、杀伤和凋亡）。利用siRNA沉默TIGIT，我们通过分析TIGIT敲低对AML患者T细胞的细胞因子释放和凋亡的影响，进一步阐明了TIGIT在T细胞免疫应答中的调节作用。结果：AML患者CD8（+）T细胞上的TIGIT表达升高，高TIGIT与原发难治性疾病和alloSCT后白血病复发相关。TIGIT（+）CD8（+）T细胞显示耗竭的表型特征，并表现出由细胞因子的低产生和对细胞凋亡的高易感性所表现的功能损伤。重要的是，他们的功能缺陷被逆转TIGIT knockdown.Conclusions：TIGIT有助于功能性T细胞损伤，并与AML的临床结果不佳。我们的研究表明，阻断TIGIT以恢复T细胞功能和抗肿瘤免疫可能代表一种新的有效的白血病治疗剂。(C)2016年AACR。
Purpose: T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is a recently identified T-cell coinhibitory receptor. In this study, we aimed to determine the clinical impact of TIGIT in patients with acute myelogenous leukemia (AML) and dissect the role of TIGIT in the pathogenesis of leukemia progression.Experimental Design: TIGIT expression on T cells from peripheral blood collected from patients with AML was examined by flow cytometry. The correlation of TIGIT expression to clinical outcomes, including rate of complete remission and relapse post-allogeneic stem cell transplantation (alloSCT) in AML patients, was analyzed. Phenotypic and functional study (cytokine release, proliferation, killing, and apoptosis) of TIGIT-expressing T cells were performed. Using siRNA to silence TIGIT, we further elucidated the regulatory role of TIGIT in the T-cell immune response by dissecting the effect of TIGIT knockdown on cytokine release and apoptosis of T cells from AML patients.Results: TIGIT expression on CD8(+) T cells is elevated in AML patients and high-TIGIT correlates with primary refractory disease and leukemia relapse post-alloSCT. TIGIT(+)CD8(+)T cells display phenotypic features of exhaustion and exhibit functional impairment manifested by low production of cytokines and high susceptibility to apoptosis. Importantly, their functional defects are reversed by TIGIT knockdown.Conclusions: TIGIT contributes to functional T-cell impairment and associates with poor clinical outcome in AML. Our study suggests that blockade of TIGIT to restore T-cell function and antitumor immunity may represent a novel effective leukemia therapeutic. (C) 2016 AACR.