Local IL-21 promotes the therapeutic activity of effector T cells by decreasing regulatory T cells within the tumor microenvironment.
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.
Kim-Schulze
Seunghee
S
The Tumor Immunology Laboratory, Division of Surgical Oncology, Columbia University, New York, New York, USA.
Kim
Hong Sung
HS
Fan
Qing
Q
Kim
Dae Won
DW
Kaufman
Howard L
HL
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007378:Interleukins / Q000235:genetics / Q000502:physiology*; D007700:Kinetics; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D000098546:Interleukin-21
D007378:Interleukins; D000098546:Interleukin-21