IL-21 activates both innate and adaptive immunity to generate potent antitumor responses that require perforin but are independent of IFN-gamma.
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.
Ma
Hak-Ling
HL
Wyeth Research, Cambridge, MA 02140, USA.
Whitters
Matthew J
MJ
Konz
Richard F
RF
Senices
Mayra
M
Young
Deborah A
DA
Grusby
Michael J
MJ
Collins
Mary
M
Dunussi-Joannopoulos
Kyriaki
K
D000276:Adjuvants, Immunologic; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005260:Female; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007110:Immunity, Active / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism / Q000502:physiology*; D016753:Interleukin-10 / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology; D053738:Interleukin-21 Receptor alpha Subunit; D015847:Interleukin-4 / Q000502:physiology; D007378:Interleukins / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D053655:Receptors, Interleukin-21; D012513:Sarcoma, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D000098546:Interleukin-21
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D006131:Growth Inhibitors; C508118:Il21r protein, mouse; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D018123:Receptors, Interleukin; D053655:Receptors, Interleukin-21; D054353:Perforin; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D000098546:Interleukin-21