Type I IFN gene delivery suppresses regulatory T cells within tumors

• Published in: Cancer gene therapy Vol. 21; no. 12; pp. 532 - 541
• Main Authors: Hashimoto, H, Ueda, R, Narumi, K, Heike, Y, Yoshida, T, Aoki, K
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-12-2014; Nature Publishing Group
• Subjects: 631/67/580; Adenoviridae - genetics; Animal models; Animals; Antitumor activity; Biomedical and Life Sciences; Biomedicine; Care and treatment; CD11c antigen; CD4 antigen; Cell activation; Cell culture; Cell death; Cell Line, Tumor; Cytokines; Dendritic cells; Disease Progression; Gene Expression; Gene Therapy; Gene transfer; Gene Transfer Techniques; Genetic aspects; Genetic Therapy; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Health aspects; Helper cells; Humans; Immunomodulation; Immunoregulation; Interferon; Interferon Type I - genetics; Interferon Type I - metabolism; Interferon-alpha - genetics; Interferon-alpha - metabolism; Interleukin 6; Interleukin 6 receptors; Interleukin-6 - metabolism; Lymphocyte Count; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Male; Methods; Mice; Microenvironments; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - therapy; original-article; Receptors, Interleukin-6 - antagonists & inhibitors; T cells; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Th17 Cells - immunology; Th17 Cells - metabolism; Tumor Burden - genetics; Tumor Burden - immunology; Tumors; α-Interferon
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/cgt.2014.60

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.