Saijo Y, Hong X, Tanaka M, Tazawa R, Liu S Q, Saijo K, Ohno T, Koike K, Ohkuda K, Satoh K, Nukiwa T
Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan.
Clin Cancer Res. 1999 May;5(5):1203-9.
Although CTLs bear main immune responses in human tumors, stable CTL clones against human lung cancer have rarely been generated. Our previous study demonstrated efficient autologous CTL induction in human gastric cancer and glioblastoma by cytokine combination of interleukin (IL)-1beta (167 IU/ml), IL-2 (67 IU/ml), IL-4 (67 IU/ml), and IL-6 (134 IU/ml). In this study, we demonstrated successful induction of autologous stable CTLs in five of six patients with lung adenocarcinoma from mixed-lymphocyte tumor culture using this cytokine combination. All CTLs revealed potent and specific killing activity against autologous target cells (over 75% in CD8+ CTLs and over 50% in CD4+ CTLs at an E:T ratio of 10 for 24 h). Using a series of antibodies, CD8+ CTLs showed to recognize tumor-specific antigens of lung cancer cells through HLA class I. In the separate experiments, failure of CTL induction from monocyte-depleted peripheral blood mononuclear cells and appearance of cells with characteristics of dendritic cells from adherent peripheral blood mononuclear cells in the culture of the same concentration of IL-1beta, IL-4, and IL-6 indicated that CTLs can be efficiently generated by this cytokine combination via possible dendritic cell induction. This is the first study of an efficient and reproducible in vitro CTL induction against human lung cancer.
尽管细胞毒性T淋巴细胞（CTL）在人类肿瘤中承担着主要免疫反应，但针对人类肺癌的稳定CTL克隆却很少被成功构建。我们之前的研究表明，通过白细胞介素（IL）-1β（167 IU/ml）、IL-2（67 IU/ml）、IL-4（67 IU/ml）和IL-6（134 IU/ml）的细胞因子组合，可在人类胃癌和胶质母细胞瘤中高效诱导自体CTL。在本研究中，我们证明了使用这种细胞因子组合，在六例肺腺癌患者中的五例通过混合淋巴细胞肿瘤培养成功诱导出了自体稳定CTL。所有CTL均显示出对自体靶细胞的强大且特异性杀伤活性（在效靶比为10的情况下作用24小时，CD8⁺CTL中超过75%，CD4⁺CTL中超过50%）。使用一系列抗体，CD8⁺CTL显示通过HLA I类识别肺癌细胞的肿瘤特异性抗原。在单独实验中，从单核细胞耗竭的外周血单核细胞诱导CTL失败，以及在相同浓度的IL-1β、IL-4和IL-6培养中，贴壁外周血单核细胞出现具有树突状细胞特征的细胞，这表明通过这种细胞因子组合可能经由诱导树突状细胞可高效产生CTL。这是第一项关于针对人类肺癌高效且可重复的体外CTL诱导的研究。
