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Intratumoral interferon-α gene transfer enhances tumor immunity after allogeneic hematopoietic stem cell transplantation

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Abstract

One of the major challenges in the treatment of solid cancers by allogenic hematopoietic stem cell transfer (alloHSCT) is the specific enhancement of antitumor immunity. Interferon (IFN) is a cytokine with pleiotropic biological functions including an immunomoduration, and our preclinical studies have shown that an intratumoral IFN-α gene transfer induced strong local tumor control and systemic tumor-specific immunity. In the present study, we examined whether the IFN-α gene transfer could enhance recognition of tumor-associated antigens by donor T cells and augment the antitumor activity of alloHSCT. First, when a mouse IFN-α adenovirus vector (Ad-mIFN) was injected into subcutaneous xenografts of syngeneic renal and colon cancer cells, tumor growth was significantly suppressed in a dose-dependent manner. A significant tumor cell death and infiltration of immune cells was recognized in the Ad-mIFN-injected tumors, and the dendrtic cells isolated from the tumors showed a strong Th1-oriented response. The antitumor effect of Ad-mIFN was then examined in a murine model of minor histocompatibility antigen-mismatched alloHSCT. The intratumoral IFN-α gene transfer caused significant tumor suppression in the alloHSCT recipients, and this suppression was evident not only in the gene-transduced tumors but also in simultaneously inoculated distant tumors which did not receive the vector injection. A cytotoxicity assay showed specific tumor cell lysis by donor T cells responding to IFN-α. Graft-versus-host disease was not exacerbated serologically or clinically in the mice treated with IFN-α. This combination strategy deserves evaluation in future clinical trials for human solid cancers.

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Acknowledgments

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 Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NiBio). H. Hara, T. Nishimoto and M. Ohashi are awardees of a Research Resident Fellowship from the Foundation for Promotion of Cancer Research.

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Authors and Affiliations

  1. Section for Studies on Host-Immune Response, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo, Tokyo, 104-0045, Japan

    Hidehiko Hara, Akihiko Kobayashi, Kenta Narumi, Atsushi Kondoh, Kimiko Yoshida, Takeshi Nishimoto & Kazunori Aoki

  2. Genetics Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo, Tokyo, 104-0045, Japan

    Masaki Ohashi, Shumpei Ohnami & Teruhiko Yoshida

  3. Department of Urology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan

    Hidehiko Hara & Eiji Higashihara

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  1. Hidehiko Hara
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  2. Akihiko Kobayashi
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Correspondence to Kazunori Aoki.

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Hara, H., Kobayashi, A., Narumi, K. et al. Intratumoral interferon-α gene transfer enhances tumor immunity after allogeneic hematopoietic stem cell transplantation. Cancer Immunol Immunother 58, 1007–1021 (2009). https://doi.org/10.1007/s00262-008-0616-0

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  • DOI: https://doi.org/10.1007/s00262-008-0616-0

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