Type I IFN gene delivery suppresses regulatory T cells within tumors

Cancer Gene Ther. 2014 Dec;21(12):532-41. doi: 10.1038/cgt.2014.60. Epub 2014 Nov 28.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Cell Line, Tumor
  • Disease Progression
  • Gene Expression
  • Gene Transfer Techniques
  • Genetic Therapy
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Humans
  • Immunomodulation
  • Interferon Type I / genetics*
  • Interferon Type I / metabolism
  • Interferon-alpha / genetics
  • Interferon-alpha / metabolism
  • Interleukin-6 / metabolism
  • Lymphocyte Count
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Male
  • Mice
  • Neoplasms / genetics*
  • Neoplasms / immunology*
  • Neoplasms / metabolism
  • Neoplasms / therapy
  • Receptors, Interleukin-6 / antagonists & inhibitors
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*
  • Th17 Cells / immunology
  • Th17 Cells / metabolism
  • Tumor Burden / genetics
  • Tumor Burden / immunology


  • Interferon Type I
  • Interferon-alpha
  • Interleukin-6
  • Receptors, Interleukin-6