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

• Published in: The Journal of immunology (1950) 2000-09, Vol.165 (5), p.2665-2670
• Main Authors: Smyth, Mark J, Taniguchi, Masaru, Street, Shayna E. A
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Disease Models, Animal; Dose-Response Relationship, Immunologic; Drug Administration Schedule; Immunity, Innate - genetics; Injections, Intraperitoneal; Interferon-gamma - deficiency; Interferon-gamma - genetics; Interferon-gamma - physiology; Interleukin-12 - administration & dosage; Interleukin-12 - physiology; Interleukin-12 - therapeutic use; Killer Cells, Natural - immunology; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Lymphocyte Depletion; Lymphoma - immunology; Lymphoma - prevention & control; Male; Melanoma, Experimental - immunology; Melanoma, Experimental - prevention & control; Melanoma, Experimental - secondary; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Transplantation; NK antigen; Perforin; Pore Forming Cytotoxic Proteins; Prostatic Neoplasms - immunology; Prostatic Neoplasms - prevention & control; T-Lymphocyte Subsets - immunology; Tumor Cells, Cultured
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.165.5.2665

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.