Local IL-21 promotes the therapeutic activity of effector T cells by decreasing regulatory T cells within the tumor microenvironment

Mol Ther. 2009 Feb;17(2):380-8. doi: 10.1038/mt.2008.249. Epub 2008 Nov 25.


The eradication of tumors by the immune system depends on the generation of antigen-specific T cells which can migrate to sites of tumor growth and maintain their effector functions despite local tumor-derived T-cell inhibitory factors. Interleukin-21 (IL-21) is an IL-2-related cytokine that has shown limited evidence of antitumor activity in murine models and early phase clinical trials. Effect of local IL-21 on T-cell responses within the tumor microenvironment, however, has not been extensively evaluated. Thus, we developed a stably transfected IL-21-secreting B16 melanoma cell line to test the effects of local IL-21 on endogenous and adoptively transferred T-cell responses. Tumors expressing IL-21 exhibited delayed growth in vivo, which was associated with an increase in activated systemic effector and memory CD8(+) T-cell responses. Local IL-21 also enhanced the therapeutic effects of adoptively transferred gp100-specific T cells and was synergistic with IL-2. The effect was also associated with an increased proliferation of local CD8(+) T cells and decreased accumulation of regulatory CD4(+)FOXP3(+) T cells within the tumor microenvironment. These data suggest that local IL-21 enhances endogenous and adoptively transferred T-cell immunity through increased effector CD8(+) T cells and decreased CD4(+) regulatory T cells in the tumor microenvironment.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Cell Proliferation
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Interleukins / genetics
  • Interleukins / physiology*
  • Kinetics
  • Melanoma / immunology
  • Melanoma / therapy
  • Mice
  • Mice, Transgenic
  • Neoplasms / immunology*
  • Neoplasms / therapy*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*


  • Interleukins
  • interleukin-21