title: In vivo antitumor activity of interleukin 21 mediated by natural killer cells.
abstract: 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.
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. gangwang@mdanderson.org
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Mary
authors.initials: M
authors.lastname: Tschoi
authors.forename: Rosanne
authors.initials: R
authors.lastname: Spolski
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Lou
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Ozaki
authors.forename: Chiguang
authors.initials: C
authors.lastname: Feng
authors.forename: Grace
authors.initials: G
authors.lastname: Kim
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
mesh_terms: D000818:Animals; D016516:CD4-CD8 Ratio; D002455:Cell Division / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005354:Fibrosarcoma / Q000235:genetics / Q000276:immunology / Q000628:therapy; D018014:Gene Transfer Techniques; D007376:Interleukin-2 / Q000097:blood / Q000378:metabolism; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D016207:Cytokines; D007376:Interleukin-2; D007378:Interleukins; D000098546:Interleukin-21