title: Type I IFN gene delivery suppresses regulatory T cells within tumors.
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.
authors.affiliation: Division of Gene and Immune Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Division of Gene and Immune Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Ueda
authors.affiliation: Division of Gene and Immune Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Narumi
authors.affiliation: Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, Chuo-ku, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Heike
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, National Cancer Center, Chuo-ku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Division of Gene and Immune Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Aoki
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D056747:Immunomodulation; D007370:Interferon Type I / Q000235:genetics* / Q000378:metabolism; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics / Q000276:immunology
chemical_list: D007370:Interferon Type I; D016898:Interferon-alpha; D015850:Interleukin-6; D019947:Receptors, Interleukin-6