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Autologous High-Killing Cytotoxic T Lymphocytes against Human Lung Cancer Are Induced Using Interleukin (IL)-1ß, IL-2, IL-4, and IL-6: Possible Involvement of Dendritic Cells¹

Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, Sendai 980-8575 [Y. S., X. H., M. T., R. T., Ke. S., T. N.]; RIKEN Cell Bank, The Institute of Physical and Chemical Research (RIKEN), Tsukuba Science City [S. Q. L., Ka. S., T. O.]; Miyagi Cancer Center, Sendai [K. K.]; and Miyagi Semine Hospital, Semine-cho, Miyagi [K. O.], Japan

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)-1ß (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-1ß, 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.

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