Two distinct effector memory cell populations of WT1 (Wilms' tumor gene 1)-specific cytotoxic T lymphocytes in acute myeloid leukemia patients
Two distinct effector memory cell populations of WT1 (Wilms' tumor gene 1)-specific cytotoxic T lymphocytes in acute myeloid leukemia patients
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急性髓系白血病患者中 WT1（维尔姆斯肿瘤基因 1）特异性细胞毒性 T 淋巴细胞的两个不同的效应记忆细胞群
DOI：
10.1007/s00262-015-1683-7
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Sugiyama H.
中科院分区：
文献类型：
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作者：
Nakae Y.;Oka Y.;Fujiki F.;Morimoto S.;Kamiya T.;Takashima S.;Nakata J.;Nishida S.;Nakajima H.;Hosen N.;Tsuboi A;Kyo T.;Oji Y.;Mizuguchi K.;Kumanogoh A.;Sugiyama H.
Wilms' tumor gene 1（WT 1）蛋白是一种很有前途的肿瘤相关抗原，可用于肿瘤免疫治疗。我们已经在750多名白血病或实体癌患者中进行了WT 1肽疫苗接种，并获得了良好的临床反应。在这项研究中，我们生成了九名接受WT 1肽疫苗治疗的急性髓性白血病患者外周血中WT 1特异性细胞毒性T淋巴细胞（CTL）的效应记忆（EM）子集的单细胞基因表达谱，以区分反应者（外周血中WT 1 mRNA水平下降至不可检测水平，下降但保持在异常水平，稳定在不可检测水平，或在WT 1疫苗接种后6个月以上与初始异常水平保持不变）的非应答者（WT 1疫苗接种后6个月内白血病母细胞和/或WT 1 mRNA水平相对于初始状态增加）。使用83个基因进行的聚类和主成分分析在WT 1疫苗接种前不能区分应答者和非应答者。然而，这些分析显示，WT 1特异性CTL的EM亚群可以分为两组：“活化”和“静止”状态;在应答者中，CTL的EM亚群转变为“静止”状态，而在非应答者中，在WT 1疫苗接种后，CTL的EM亚群转变为“活化”状态。这些结果首次证明了AML患者中WT 1特异性CTL存在两种不同的EM状态，每种状态都是应答者或非应答者的特征，并提出了使用先进的基因表达谱分析来明确区分WT 1疫苗接种前应答者和非应答者的可能性。
Wilms’ tumor gene 1 (WT1) protein is a promising tumor-associated antigen for cancer immunotherapy. We have been performing WT1 peptide vaccination with good clinical responses in over 750 patients with leukemia or solid cancers. In this study, we generated single-cell gene-expression profiles of the effector memory (EM) subset of WT1-specific cytotoxic T lymphocytes (CTLs) in peripheral blood of nine acute myeloid leukemia patients treated with WT1 peptide vaccine, in order to discriminate responders (WT1mRNA levels in peripheral blood decreased to undetectable levels, decreased but stayed at abnormal levels, were stable at undetectable levels, or remained unchanged from the initial abnormal levels more than 6 months after WT1 vaccination) from non-responders (leukemic blast cells and/orWT1mRNA levels increased relative to the initial state within 6 months of WT1 vaccination) prior to WT1 vaccination. Cluster and principal component analyses performed using 83 genes did not discriminate between responders and non-responders prior to WT1 vaccination. However, these analyses revealed that EM subset of WT1-specific CTLs could be divided into two groups: the “activated” and “quiescent” states; in responders, EM subset of the CTLs shifted to the “quiescent” state, whereas in non-responders, those shifted to the “activated” state following WT1 vaccination. These results demonstrate for the first time the existence of two distinct EM states, each of which was characteristic of responders or non-responders, of WT1-specific CTLs in AML patients, and raises the possibility of using advanced gene-expression profile analysis to clearly discriminate between responders and non-responders prior to WT1 vaccination.