The anti-tumor activity of IL-12: mechanisms of innate immunity that are model and dose dependent.
IL-12 has been demonstrated to have potent anti-tumor activities in a variety of mouse tumor models, but the relative roles of NK, NKT, and T cells and their effector mechanisms in these responses have not been fully addressed. Using a spectrum of gene-targeted or Ab-treated mice we have shown that for any particular tumor model the effector mechanisms downstream of IL-12 often mimic the natural immune response to that tumor. For example, metastasis of the MHC class I-deficient lymphoma, EL4-S3, was strictly controlled by NK cells using perforin either naturally or following therapy with high-dose IL-12. Intriguingly, in B16F10 and RM-1 tumor models both NK and NKT cells contribute to natural protection from tumor metastasis. In these models, a lower dose of IL-12 or delayed administration of IL-12 dictated a greater relative role of NKT cells in immune protection from tumor metastasis. Overall, both NK and NKT cells can contribute to natural and IL-12-induced immunity against tumors, and the relative role of each population is tumor and therapy dependent.
Smyth
M J
MJ
Cancer Immunology, Peter MacCallum Cancer Institute, St. Andrews Place, East Melbourne, Victoria, Australia. m.smyth@pmci.unimelb.edu.au
Taniguchi
M
M
Street
S E
SE
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D004334:Drug Administration Schedule; D007113:Immunity, Innate / Q000235:genetics; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000502:physiology / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D008212:Lymphocyte Depletion; D008223:Lymphoma / Q000276:immunology / Q000517:prevention & control; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011471:Prostatic Neoplasms / Q000276:immunology / Q000517:prevention & control; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D018664:Interleukin-12; D007371:Interferon-gamma