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Tumor Cells Loaded with -Galactosylceramide Induce Innate NKT and NK Cell-Dependent Resistance to Tumor Implantation in Mice¹

Kanako Shimizu^*, Akira Goto^*, Mikiko Fukui^*, Masaru Taniguchi and Shin-ichiro Fujii^2,*

^* Research Unit for Cellular Immunotherapy, and Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology, Kanagawa, Japan

Dendritic cells (DCs) loaded with -galactosylceramide (-GalCer) are known to be active APCs for the stimulation of innate NKT and NK cell responses in vivo. In this study, we evaluated the capacity of non-DCs to present -GalCer in vitro and in vivo, particularly tumor cells loaded with -GalCer (tumor/Gal). Even though the tumor cells lacked expression of CD40, CD80, and CD86 costimulatory molecules, the i.v. injection of tumor/Gal resulted in IFN- secretion by NKT and NK cells. These innate responses to tumor/Gal, including the induction of IL-12p70, were comparable to or better than -GalCer-loaded DCs. B16 melanoma cells that were stably transduced to express higher levels of CD1d showed an increased capacity relative to wild-type B16 cells to present -GalCer in vivo. Three different tumor cell lines, when loaded with -GalCer, failed to establish tumors upon i.v. injection, and the mice survived for at least 6 mo. The resistance against tumor cells was independent of CD4 and CD8 T cells but dependent upon NKT and NK cells. Mice were protected from the development of metastases if the administration of live B16 tumor cells was followed 3 h or 3 days later by the injection of CD1d^high--GalCer-loaded B16 tumor cells with or without irradiation. Taken together, these results indicate that tumor/Gal are effective APCs for innate NKT and NK cell responses, and that these innate immune responses are able to resist the establishment of metastases in vivo.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Ministry of Education, Science, Sports, and Culture of Japan (to K.S. and S.-i.F.).

² Address correspondence and reprint requests to Dr. Shin-ichiro Fujii, Research Unit for Cellular Immunotherapy, RIKEN Research Center for Allergy and Immunology, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. E-mail address: fujiis{at}rcai.riken.jp

³ Abbreviations used in this paper: -GalCer, -galactosylceramide; DC, dendritic cell; tumor/Gal, tumor cells loaded with -GalCer; DC/Gal, DC loaded with -GalCer; B16/Gal, B16 cells loaded with -GalCer.

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