Nakae Yoshiki, Oka Yoshihiro, Fujiki Fumihiro, Morimoto Soyoko, Kamiya Toshio, Takashima Satoshi, Nakata Jun, Nishida Sumiyuki, Nakajima Hiroko, Hosen Naoki, Tsuboi Akihiro, Kyo Taiichi, Oji Yusuke, Mizuguchi Kenji, Kumanogoh Atsushi, Sugiyama Haruo
Departments of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Cancer Immunol Immunother. 2015 Jul;64(7):791-804. doi: 10.1007/s00262-015-1683-7. Epub 2015 Apr 3.
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 (WT1 mRNA 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/or WT1 mRNA 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.
肾母细胞瘤基因1（WT1）蛋白是癌症免疫治疗中一种很有前景的肿瘤相关抗原。我们一直在对750多名白血病或实体癌患者进行WT1肽疫苗接种，并取得了良好的临床反应。在本研究中，我们生成了9名接受WT1肽疫苗治疗的急性髓系白血病患者外周血中WT1特异性细胞毒性T淋巴细胞（CTL）效应记忆（EM）亚群的单细胞基因表达谱，以便在WT1疫苗接种前区分反应者（外周血中WT1 mRNA水平降至检测不到的水平、下降但仍处于异常水平、稳定在检测不到的水平或在WT1疫苗接种后6个月以上相对于初始异常水平保持不变）和无反应者（白血病原始细胞和/或WT1 mRNA水平在WT1疫苗接种后6个月内相对于初始状态升高）。使用83个基因进行的聚类分析和主成分分析在WT1疫苗接种前未能区分反应者和无反应者。然而，这些分析表明，WT1特异性CTL的EM亚群可分为两组：“激活”状态和“静止”状态；在反应者中，CTL的EM亚群转变为“静止”状态，而在无反应者中，WT1疫苗接种后这些亚群转变为“激活”状态。这些结果首次证明了急性髓系白血病患者中WT1特异性CTL存在两种不同的EM状态，每种状态分别是反应者或无反应者的特征，并提高了在WT1疫苗接种前使用先进的基因表达谱分析来明确区分反应者和无反应者的可能性。
