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The Journal of Immunology, 00, 165: 2665-2670.
Copyright © 00 by The American Association of Immunologists

The Anti-Tumor Activity of IL-12: Mechanisms of Innate Immunity That Are Model and Dose Dependent1

Mark J. Smyth2,*, Masaru Taniguchi{dagger} and Shayna E. A. Street*

* Cancer Immunology, Peter MacCallum Cancer Institute, St. Andrews Place, East Melbourne, Victoria, Australia; {dagger} Division of Molecular Immunology, Center of Biomedical Sciences, Chiba University School of Medicine, Chiba, Japan

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.




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