1. IL-21 activates both innate and adaptive immunity to generate potent antitumor responses that require perforin but are independent of IFN-gamma.
- Author
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Ma HL, Whitters MJ, Konz RF, Senices M, Young DA, Grusby MJ, Collins M, and Dunussi-Joannopoulos K
- Subjects
- Adjuvants, Immunologic, Animals, Antigens, Neoplasm immunology, Cancer Vaccines genetics, Cancer Vaccines immunology, Cancer Vaccines metabolism, Cell Division genetics, Cell Division immunology, Cytotoxicity, Immunologic genetics, Female, Growth Inhibitors genetics, Growth Inhibitors metabolism, Immunity, Active genetics, Immunity, Innate genetics, Interferon-gamma metabolism, Interleukin-10 physiology, Interleukin-12 physiology, Interleukin-21 Receptor alpha Subunit, Interleukin-4 physiology, Interleukins genetics, Interleukins metabolism, Melanoma, Experimental genetics, Melanoma, Experimental metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Nude, Mice, SCID, Perforin, Pore Forming Cytotoxic Proteins, Receptors, Interleukin deficiency, Receptors, Interleukin genetics, Receptors, Interleukin physiology, Receptors, Interleukin-21, Sarcoma, Experimental genetics, Sarcoma, Experimental immunology, Sarcoma, Experimental metabolism, Sarcoma, Experimental therapy, T-Lymphocytes, Cytotoxic immunology, Transduction, Genetic, Tumor Cells, Cultured, Cancer Vaccines administration & dosage, Growth Inhibitors physiology, Interferon-gamma physiology, Interleukins administration & dosage, Interleukins physiology, Melanoma, Experimental immunology, Melanoma, Experimental therapy, Membrane Glycoproteins physiology
- Abstract
IL-21 is a key factor in the transition between innate and adaptive immune responses. We have used the cytokine gene therapy approach to study the antitumor responses mediated by IL-21 in the B16F1 melanoma and MethA fibrosarcoma tumor models in mice. Retrovirally transduced tumor cells secreting biologically functional IL-21 have growth patterns in vitro similar to that of control green fluorescent protein-transduced cells, but are completely rejected in vivo. We show that IL-21 activates NK and CD8(+) T cells in vivo, thus mediating complete rejection of poorly immunogenic tumors. Rejection of IL-21-secreting tumors requires the presence of cognate IL-21R and does not depend on CD4(+) T cell help. Interestingly, perforin, but not IFN-gamma or other major Th1 and Th2 cytokines (IL-12, IL-4, or IL-10), is required for the IL-21-mediated antitumor response. Moreover, IL-21 results in 50% protection and 70% cure of nonimmunogenic tumors when given before and after tumor challenge, respectively, in C57BL/6 mice. We conclude that IL-21 immunotherapy warrants clinical evaluation as a potential treatment for cancer.
- Published
- 2003
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