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Dendritic cells transduced with gp100 gene by RGD fiber-mutant adenovirus vectors are highly efficacious in generating anti-B16BL6 melanoma immunity in mice

Gene Therapy volume 10, pages 1891–1902 (2003)Cite this article

Abstract

Dendritic cells (DCs) are the most potent professional antigen-presenting cells for the initiation of antigen-specific immune responses, and antigen-loaded DCs have been regarded as promising vaccines in cancer immunotherapy. We previously demonstrated that RGD fiber-mutant adenovirus vector (AdRGD) could attain highly efficient gene transduction into human and murine DCs. The aim of the present study is to demonstrate the predominance of ex vivo genetic DC manipulation using AdRGD in improving the efficacy of DC-based immunotherapy targeting gp100, a melanoma-associated antigen (MAA). Vaccination with murine bone marrow-derived DCs transduced with AdRGD encoding gp100 (AdRGD-gp100/mBM-DCs) dramatically improved resistance to B16BL6 melanoma challenge and pulmonary metastasis as compared with immunization with conventional Ad-gp100-transduced mBM-DCs. The improvement in antimelanoma effects upon immunization with AdRGD-gp100/mBM-DCs correlated with enhanced cytotoxic activities of natural killer (NK) cells and B16BL6-specific cytotoxic T lymphocytes (CTLs). Furthermore, in vivo depletion analysis demonstrated that CD8+ CTLs and NK cells were the predominant effector cells responsible for the anti-B16BL6 immunity induced by vaccination with AdRGD-gp100/mBM-DCs, and that helper function of CD4+ T cells was necessary for sufficiently eliciting effector activity. These findings clearly revealed that highly efficient MAA gene transduction to DCs by AdRGD could greatly improve the efficacy of DC-based immunotherapy against melanoma.

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Acknowledgements

We are grateful to Dr Hirofumi Hamada (Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan) for providing pAx1-CA h-gp100, to Dr Hiroshi Yamamoto (Department of Immunology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan) for providing GK1.5 and 53-6.72 hybridoma cells, to Drs Hitoshi Kikutani and Atsushi Kumanogoh (Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan) for technical advice about the mBM-DC preparation, and to Takashi Tsuda, Asako Matsubara, Emiko Inoue, Maki Okubo, Masaya Nishida, and Miyuki Yamanaka (Department of Biopharmaceutics, Kyoto Pharmaceutical University, Kyoto, Japan) for technical assistance.

The present study was supported in part by a Grant-in-Aid for the Encouragement of Young Scientists (13771394) from the Japan Society for the Promotion of Science; by the Research on Health Sciences focusing on Drug Innovation from The Japan Health Sciences Foundation; by grants from the Bioventure Development Program of the Ministry of Education, Culture, Sports, Science and Technology of Japan; by the Frontier Research Program of the Ministry of Education, Culture, Sports, Science and Technology of Japan; by the Science Research Promotion Fund of the Japan Private School Promotion Foundation; by Uehara Memorial Foundation; and by grants from the Ministry of Health and Welfare in Japan.

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Authors and Affiliations

  1. Department of Biopharmaceutics, Kyoto Pharmaceutical University, Kyoto, Japan

    N Okada, Y Masunaga, S Iiyama, N Mori, A Sasaki, T Fujita & A Yamamoto

  2. Department of Pharmaceutics, School of Pharmaceutical Sciences, Mukogawa Women's University, Hyogo, Japan

    Y Okada

  3. Division of Cellular and Gene Therapy Products, National Institute of Health Sciences, Tokyo, Japan

    H Mizuguchi

  4. Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

    S Nakagawa & T Mayumi

  5. National Institute of Health Sciences, Tokyo, Japan

    T Hayakawa

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Okada, N., Masunaga, Y., Okada, Y. et al. Dendritic cells transduced with gp100 gene by RGD fiber-mutant adenovirus vectors are highly efficacious in generating anti-B16BL6 melanoma immunity in mice. Gene Ther 10, 1891–1902 (2003). https://doi.org/10.1038/sj.gt.3302090

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