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The antitumor activity of IL-12: mechanisms of innate immunity that are model and dose

By Mark J. Smyth, Masaru Taniguchi and Shayna E. A. Street


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 genetargeted 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. The Journal of Immunology, 2000, 165: 2665–2670. Interleukin-12 was first identified and isolated as an NK cell stimulatory factor (1). Compared with other cytokines, it has a unique 70-kDa heterodimeric structure composed of two covalently linked p35 and p40 subunits, both of which are required for biological activities (1, 2). IL-12 is produced principally by APC, such as monocytes, macrophages, and dendritic cells. In addition to a stimulatory effect on NK cells, IL-12 activates cytotoxic T cells (3, 4), differentiates CD4 � lymphocytes (5, 6), plays an important role in regulating the balance between type I and type 2 responses of Th lymphocytes (7, 8), primes macrophages for NO production (9), and possesses IFN-�-dependent anti-angiogenic activity (10, 11). IL-12 has been shown to possess potent anti-tumor activity in a wide variety of murine tumor models (2, 12–15). Activity has been demonstrated against tumors of various histologies, including carcinomas arising from the colon (CT26, MC38), kidney (Renca), and lung (3LL); carcinogen-induced sarcoma lines (including the methylcholanthrene-induced series); and melanoma (B16F10 an

Year: 2000
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