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[Cancer Research 63, 9016-9022, December 15, 2003]
© 2003 American Association for Cancer Research

Immunology

In Vivo Antitumor Activity of Interleukin 21 Mediated by Natural Killer Cells

Gang Wang1, Mary Tschoi1, Rosanne Spolski2, Yanyan Lou1, Katsutoshi Ozaki2, Chiguang Feng1, Grace Kim1, Warren J. Leonard2 and Patrick Hwu1

1 Center for Cancer Research, National Cancer Institute, and
2 Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

Immunotherapy with high-dose interleukin (IL) 2 has been shown to successfully treat tumors in animal models and cause dramatic tumor regressions in some patients with metastatic melanoma, renal cell carcinoma, and non-Hodgkin’s lymphoma. However, toxicity associated with IL-2 administration has compromised its widespread use in the clinic. IL-21 is a more recently discovered cytokine produced by activated CD4+ T cells that shares significant sequence homology to IL-2, IL-4, and IL-15. Because IL-21 and IL-2 and their receptors share significant sequence similarities and both cytokines can stimulate T and natural killer (NK) cells, we sought to study whether IL-21, like IL-2, exhibits antitumor effects in vivo. In this study, we treated established s.c. tumor in mice by systemically administering plasmid DNA encoding murine IL-21 using a hydrodynamics-based gene delivery technique. Administration of IL-21 plasmid DNA resulted in high levels of circulating IL-21 in vivo. Treatment of tumor-bearing mice with IL-21 plasmid DNA significantly inhibited the growth of B16 melanoma and MCA205 fibrosarcoma in a dose-dependent manner without significant toxicity and increased the survival rate, compared with mice treated with control plasmid DNA. In vivo depletion of either CD4+ or CD8+ T cells did not affect IL-21-mediated antitumor activity. However, depletion of NK cells completely abolished IL-21-induced tumor inhibition. Consistent with this, the antitumor activity of IL-21 seemed to be mediated through enhanced cytolytic activity of NK cells. Our study suggests that IL-21 has significant antitumor activity and may have therapeutic potentials as an antitumor agent in the clinic.




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