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The Journal of Immunology, 2003, 171: 608-615.
Copyright © 2003 by The American Association of Immunologists

IL-21 Activates Both Innate and Adaptive Immunity to Generate Potent Antitumor Responses that Require Perforin but Are Independent of IFN-{gamma}1

Hak-Ling Ma*, Matthew J. Whitters*, Richard F. Konz*, Mayra Senices*, Deborah A. Young*, Michael J. Grusby{dagger}, Mary Collins* and Kyriaki Dunussi-Joannopoulos2,*

* Wyeth Research, Cambridge, MA 02140; and {dagger} Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115

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.




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