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Potentiation of antitumor effect of NKT cell ligand, α-galactosylceramide by combination with IL-12 on lung metastasis of malignant melanoma cells1

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Abstract

The combined therapeutic effect of natural killer T (NKT) cell ligand α-galactosylceramide (α-GalCer) and IL-12 against highly metastatic B16-BL6-HM melanoma cells was investigated. In comparison with a single administration of α-GalCer or IL-12, the combined treatment of tumor-bearing mice with α-GalCer plus IL-12 caused a super-induction of serum IFN-γ levels, though α-GalCer-induced IL-4 production was rather inhibited. In parallel with the augmented IFN-γ production, the natural killing activity against YAC-1 cells and syngeneic B16- BL6-HM melanoma was greatly augmented by the combined therapy. The major effector cells responsible for natural killing activity induced by α-GalCer plus IL- 12 were enriched in both NK1.1+TCRαβ+ NKT cells and NK1.1+TCRαβ− NK cells. The preventing effect of α-GalCer or IL-12 alone against lung metastasis of B16-BL6-HM was also enhanced by the combination therapy. The antitumor activity of α-GalCer was totally abolished in NKT-deficient mice. However, IL- 12-induced antitumor activity was not eliminated in NKT-deficient mice though it was inhibited by anti-asialo GM1 Ab treatment. These findings suggested that α-GalCer synergistically act with IL-12 to activate both NKT cells and NK cells, which may play a critical role in the strong prevention of distant tumor metastasis at early stages of tumor-bearing. These data will provide a novel tool for the prevention of tumor metastasis using NKT-specific ligands α-GalCer and IL-12.

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Authors and Affiliations

  1. Section of Genetic Engineering, Research Center for Genetic Engineering and Cell Transplantation, Japan

    Minoru Nakui, Akio Ohta, Masashi Sekimoto, Marimo Sato, Kenji Iwakabe, Takashi Yahata, Hidemitsu Kitamura & Takashi Nishimura

  2. Department of Surgery, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, 259-1193, Japan

    Minoru Nakui & Hiroyasu Makuuchi

  3. Division of Immunoreg-ulation, Institute for Genetic Medicine, Hokkaido University, Kita-ku, Sapporo, 060-0815, Japan

    Akio Ohta, Toshiaki Koda & Toshiaki Koda

  4. CREST (Core Research for Evolutional Science and Technology) Project and Department of Molecular Immunology, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan

    Tetsu Kawano & Masaru Taniguchi

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  1. Minoru Nakui
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Nakui, M., Ohta, A., Sekimoto, M. et al. Potentiation of antitumor effect of NKT cell ligand, α-galactosylceramide by combination with IL-12 on lung metastasis of malignant melanoma cells1. Clin Exp Metastasis 18, 147–153 (2000). https://doi.org/10.1023/A:1006715221088

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