CD8+ T cells expressing both PD-1 and TIGIT but not CD226 are dysfunctional in acute myeloid leukemia (AML) patients
CD8+ T cells expressing both PD-1 and TIGIT but not CD226 are dysfunctional in acute myeloid leukemia (AML) patients
复制标题
急性髓性白血病 (AML) 患者中同时表达 PD-1 和 TIGIT 但不表达 CD226 的 CD8( ) T 细胞功能失调
DOI：
10.1016/j.clim.2017.08.021
复制
发表时间：
2018-05-01
影响因子：
8.6
通讯作者：
Shen, Erxia
中科院分区：
文献类型：
--
作者：
Wang, Mengjie;Bu, Jin;Shen, Erxia
急性髓性白血病（AML）是成人中最常见的白血病类型之一，总体预后较差，治疗管理非常有限。免疫检查点阻断PD-1单独或联合其他免疫检查点阻断在小鼠AML模型中通过改善抗白血病CDR+ T细胞功能获得了令人印象深刻的效果，这极大地促进了利用联合免疫检查点抑制剂治疗AML患者的策略。然而，这些免疫检查点受体（如共抑制受体PD-1和TIGIT以及共刺激受体CD226）在AML患者T细胞中的表达谱尚未明确定义。在这里，我们定义了新诊断的AML患者和健康对照（hc）外周血（PB）中的CD8（+）和CD4(+) T细胞亚群。我们观察到，在AML患者中，PD-1和TIGIT-表达CD8(+) T细胞的频率增加，而cd226表达CD8(+) T细胞的频率减少。对这些CD8(+) T细胞的进一步分析显示，一种独特的CD8(+) T细胞亚群表达PD-1和TIGIT，但CD226水平较低，与诱导化疗后未能实现缓解和FLT3-ITD突变相关，FLT3-ITD突变预测AML患者临床预后不良。重要的是，这些PD-1(+)TIGIT(+) CD226(-)CD8(+)T细胞功能失调，细胞内ifn - γ和tnf - α的表达低于hcc中的相应细胞。因此，我们的研究表明，独特的CD8(+)T细胞亚群PD-1(+)TIGIT(+) CD226(-)CD8(+)T细胞频率的增加与AML患者的CD8(+)T细胞功能障碍和临床预后不良有关，这可能揭示关键的诊断或预后生物标志物，并指导更有效的治疗策略。(C) 2017年Elsevier Inc.出版。
Acute myeloid leukemia (AML) is one of the most common types of leukemia among adults with an overall poor prognosis and very limited treatment management. Immune checkpoint blockade of PD-1 alone or combined with other immune checkpoint blockade has gained impressive results in murine AML models by improving anti-leukemia CDR+ T cell function, which has greatly promoted the strategy to utilize combined immune checkpoint inhibitors to treat AML patients. However, the expression profiles of these immune checkpoint receptors, such as co-inhibitory receptors PD-1 and TIGIT and co-stimulatory receptor CD226, in T cells from AML patients have not been clearly defined. Here we have defined subsets of CD8(+) and CD4(+) T cells in the peripheral blood (PB) from newly diagnosed AML patients and healthy controls (HCs). We have observed increased frequencies of PD-1- and TIGIT- expressing CD8(+) T cells but decreased occurrence of CD226-expressing CD8(+) T cells in AML patients. Further analysis of these CD8(+) T cells revealed a unique CD8(+) T cell subset that expressed PD-1 and TIGIT but displayed lower levels of CD226 was associated with failure to achieve remission after induction chemotherapy and FLT3-ITD mutations which predict poor clinical prognosis in AML patients. Importantly, these PD-1(+)TIGIT(+) CD226(-)CD8(+)T cells are dysfunctional with lower expression of intracellular IFN-gamma and TNF-alpha than their counterparts in HCs. Therefore, our studies revealed that an increased frequency of a unique CD8(+) T cell subset, PD-1(+)TIGIT(+) CD226(-)CD8(+)T cells, is associated with CD8(+)T cell dysfunction and poor clinical prognosis of AML patients, which may reveal critical diagnostic or prognostic biomarkers and direct more efficient therapeutic strategies. (C) 2017 Published by Elsevier Inc.