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In vivo delivery of interferon-α gene enhances tumor immunity and suppresses immunotolerance in reconstituted lymphopenic hosts

Gene Therapy volume 19, pages 34–48 (2012)Cite this article

Abstract

T cells recognize tumor-associated antigens under the condition of lymphopenia-induced homeostatic proliferation (HP); however, HP-driven antitumor responses gradually decay in association with tumor growth. Type I interferon (IFN) has important roles in regulating the innate and adaptive immune system. In this study we examined whether a tumor-specific immune response induced by IFN-α could enhance and sustain HP-induced antitumor immunity. An intratumoral IFN-α gene transfer resulted in marked tumor suppression when administered in the early period of syngeneic hematopoietic stem cell transplantation (synHSCT), and was evident even in distant tumors that were not transduced with the IFN-α vector. The intratumoral delivery of the IFN-α gene promoted the maturation of CD11c+ cells in the tumors and effectively augmented the antigen-presentation capacity of the cells. An analysis of the cytokine profile showed that the CD11c+ cells in the treated tumors secreted a large amount of immune-stimulatory cytokines including interleukin (IL)-6. The CD11c+ cells rescued effector T-cell proliferation from regulatory T-cell-mediated suppression, and IL-6 may have a dominant role in this phenomenon. The intratumoral IFN-α gene transfer creates an environment strongly supporting the enhancement of antitumor immunity in reconstituted lymphopenic recipients through the induction of tumor-specific immunity and suppression of immunotolerance.

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Acknowledgements

This work was supported in part by a grant-in-aid for the 3rd Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan, by grants-in-aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan and by the program for promotion of Foundation Studies in Health Science of the National Institute of Biomedical Innovation (NIBIO) and by Kobayashi Foundation for Cancer Research. H Hara and T Udagawa are awardees of a Research Resident Fellowship from the Foundation for Promotion of Cancer Research. We thank Vical Incorporated for providing the DMRIE/DOPE liposome.

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Authors and Affiliations

  1. Division of Gene and Immune Medicine, National Cancer Center Research Institute, Tokyo, Japan

    K Narumi, T Udagawa, A Kondoh, A Kobayashi, H Hara, Y Ikarashi & K Aoki

  2. Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan

    S Ohnami & T Yoshida

  3. Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan

    F Takeshita & T Ochiya

  4. Department of Internal Medicine, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan

    K Narumi, T Okada & M Yamagishi

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  1. K Narumi
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  2. T Udagawa
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Correspondence to K Aoki.

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Narumi, K., Udagawa, T., Kondoh, A. et al. In vivo delivery of interferon-α gene enhances tumor immunity and suppresses immunotolerance in reconstituted lymphopenic hosts. Gene Ther 19, 34–48 (2012). https://doi.org/10.1038/gt.2011.73

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  • DOI: https://doi.org/10.1038/gt.2011.73

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