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Type I IFN gene delivery suppresses regulatory T cells within tumors

Cancer Gene Therapy volume 21, pages 532–541 (2014)Cite this article

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Abstract

Type I interferon (IFN) is a pleiotropic cytokine regulating the cancer cell death and immune response. IFN-α can, as we have also reported, effectively induce an antitumor immunity by the activation of tumor-specific T cells and maturation of dendritic cells in various animal models. Unknown, however, is how the type I IFN alters the immunotolerant microenvironment in the tumors. Here, we found that intratumoral IFN-α gene transfer significantly decreased the frequency of regulatory T cells (Tregs) per CD4+ T cells in tumors. The concentration of a Treg-inhibitory cytokine, interleukin (IL)-6, was correlated with the IFN-α expression level in tumors, and intratumoral CD11c+ cells produced IL-6 in response to IFN-α stimulation. To confirm the role of IL-6 in the suppression of Tregs in tumors, an anti-IL-6 receptor antibody was administered in IFN-α-treated mice. The antibody increased the frequency of Tregs in the tumors, and attenuated systemic tumor-specific immunity induced by IFN-α. Furthermore, the IFN-α-mediated IL-6 production increased the frequency of Th17 cells in the tumors, which may be one of the mechanisms for the reduction of Tregs. The study demonstrated that IFN-α gene delivery creates an environment strongly supporting the enhancement of antitumor immunity through the suppression of Tregs.

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Acknowledgements

We thank Chugai Pharmaceutical Co. for providing the MR16-1 antibody. 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, grants-in-aid for research from the Ministry of Health, Labour and Welfare of Japan, by the program for promotion of Foundation Studies in Health Science of the National Institute of Biomedical Innovation (NIBIO), and by the National Cancer Center Research and Development Fund (23-A-38 and 23-A-2).

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Authors and Affiliations

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

    H Hashimoto, R Ueda, K Narumi & K Aoki

  2. Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, Chuo-ku, Tokyo, Japan

    Y Heike

  3. Division of Genetics, National Cancer Center Research Institute, National Cancer Center, Chuo-ku, Tokyo, Japan

    T Yoshida

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  1. H Hashimoto
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Correspondence to K Aoki.

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Hashimoto, H., Ueda, R., Narumi, K. et al. Type I IFN gene delivery suppresses regulatory T cells within tumors. Cancer Gene Ther 21, 532–541 (2014). https://doi.org/10.1038/cgt.2014.60

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