615. Anti-Tumor Activities of IL-12 and IL-23 Are Mediated by Similar, yet Divergent, Effector Mechanisms

Abstract

Th1-polarizing cytokine IL-12 exhibits potent anti-tumor activity in multiple cancer models; however, therapeutic use of this cytokine is limited due to severe IFN-|[gamma]|-mediated toxicity. To reduce the amount of IL-12 needed to elicit a therapeutic response, and thereby decrease associated toxicity, it is necessary to characterize novel cytokines to use in conjunction with IL-12. Newly described IL-12 family member IL-23 shares the IL-12 p40 subunit and promotes Th1 immunity by specifically stimulating proliferation of memory CD4+ T-cells. We propose that adenoviral delivery of IL-23 into the tumor microenvironment will result in tumor rejection and generation of tumor-specific anti-tumor immunity utilizing mechanisms similar to IL-12. To establish the anti-tumor activity of IL-23, C57BL/6 mice bearing 7-day MCA205 fibrosarcoma tumors were treated with adenovirus expressing either IL-12 (Ad.IL-12) or 23 (Ad.IL- 23). Ad.IL-23 treatment resulted in tumor rejection in the majority of mice, elicited protective immunity and had no associated toxicity. To determine if IL-12 and IL-23 employ similar anti-tumor mechanisms, mice deficient in various cytokines and effector cells were inoculated with MCA205 tumors and treated with Ad.IL-12 or Ad.IL-23. IL-23 anti-tumor activity was found to be independent of IL-17, but completely dependent on perforin, Fas ligand, CD8+ T-cells, CD4+ T-cells, IFN-|[gamma]| and IL-12/23 p40. IL-12 anti-tumor activity was independent of Fas ligand, perforin and IL-17, but, like IL-23, completely dependent on IFN-|[gamma]| and CD8+ T-cells. Therefore, IL-12 activity appears to be mediated primarily by CD8+ T-cells and IFN-|[gamma]|, while IL-23 utilizes Fas ligand and perforin in addition to IFN-|[gamma]|, CD4+ and CD8+ T-cells to eradicate tumors. We currently are examining the possible synergy between Ad.IL-12 and Ad.IL-23 in conferring anti-tumor effects.