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 varie ty of mouse tumor models, but the relative roles of NK, NKT, and T cells an d their effector mechanisms in these responses have not been fully addresse d. 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, metasta sis 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 c ells contribute to natural protection from tumor metastasis, In these model s, a lower dose of IL-12 or delayed administration of IL-12 dictated a grea ter 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 turner and therapy dependent.