DOI: 10.1097/01.cji.0000190989.61836.e9
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Issn Print: 1524-9557
Publication Date: 2005/11/01
IL-18 plus IL-12 Decreases Liver Metastases Through An NK Cell, IFN-γ Dependent Mechanism and Overcomes NK/T Cell Mediated Suppression
Jeff Subleski; Timothy C Back; John R Ortaldo; Robert H Wiltrout
+ Author Information
Author Information: Laboratory of Experimental Immunology, NCI-CCR, Frederick, MD;
Excerpt
The liver is a major site for metastasizing malignancies. We examined the anti-tumor activity of IL-18 and/or IL-12 cytokines using a mouse liver tumor model. Treating mice with IL-18/IL-12 significantly reduced the number of tumor nodules in the liver then did either of the single agents alone. As expected, IL-18/IL-12 stimulated a synergistic increase in systemic IFN-? in tumor bearing mice. The anti-tumor activity of IL-18/IL-12 therapy was abolished in IFN-γ(−/−) mice. Using intracellular staining, NK and NK/T cells were identified as the major producers of IFN-γ in the liver of mice treated with IL-18 and/or IL-12. Liver NK cells were increased with daily treatment of mice with IL-18/IL-12 whereas liver NK/T cells were diminished by this treatment. The Depletion of NK cells with anti-asGM1 resulted in a partial loss of the anti-tumor activity of IL-18/IL-12 therapy. In contrast, depletion of NK/T cells with βGalCer decreased the number of liver tumor nodules in vehicle and IL-18 treatment group, and CD1d(−/−) mice, which lack NK/T cells, had increased anti-tumor activity among all treatment groups. Our data suggest that the IL-18/IL-12 induced anti-tumor activity in mice is the result of a synergistic induction of IFN-γ, the augmentation of effector NK cells and a significant reduction of immunosuppressive NK/T cells.
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