Abstract 388: Inhibition of IL-17 in tumor tissue suppressed tumor growth via anti-angiogenesis and CTL activation

Abstract

Abstract [Purpose]It remains controversial whether IL-17 promotes or inhibits cancer progression in tumor bearing mice. We hypothesized that IL-17 locally produced in tumor microenvironment had an important role on tumor growth. Therefore, we investigated inhibition of IL-17 by siRNA in only tumor sites using wild type mice have an effect on tumor progression.[Methods]Adenoviral vector encoding the siRNA against mouse IL-17 gene (Ad-IL-17 siRNA) was generated by the COS-TPC method. MC38 cells or B16 cells were inoculated subcutaneously into C57BL/6 mice, and at day 5, 8, 11 or at day 7,10,13 Ad-IL-17 siRNA with 1 × 109 MOI were injected intratumorally into mice. [Results]Intratumoral injection of Ad-IL-17 siRNA significantly suppressed tumor growth in both tumor models compared with control mice. We confirmed that intratumoral administration of Ad-IL17 siRNA completely suppressed endogenous IL-17 protein expression in tumor sites. To investigate the mechanisms of tumor growth suppression by inhibition of IL-17, in term of the angiogenesis we performed immunohistochemical staining of CD31 and MMP-9. Intratumoral injection of Ad-IL-17 siRNA significantly suppressed CD31 expression and MMP-9 expression in tumor tissue. Next, to investigate the effect of the inhibition of IL-17 in tumor tissue on systemic and local anti-tumor immunity, we assessed CTL activities of CD8+ T cells from splenocytes or tumor-infiltrating lymphocytes (TILs). The cytotoxic activities in CD8+ T cells from TILs in mice treated with intratumoral injection of Ad-IL-17 siRNA were significantly higher than those in control mice, but not splenocytes. To identify why the mechanism of the enhanceing effect on CTL activity by the inhibition of IL-17, especially in tumor microenvironment, we examined the Th1/Th2 phenotype from splenocytes or TILs. The levels of IFNγ+ CD4+ T cells from TILs were significantly higher in Ad-IL-17 siRNA-injected mice compared with those in control mice, but not splenocytes. On the other hand IL-4+ CD4+ T cells from TILs and splenocytes were similar levels in both mice.[Conclusion]The suppression of IL-17 expression in tumor tissues improved the immunological tumor microenvironment by shifting to Th1 dominant environment, resulting in CTL activation in tumor sites. It was suggested that the blockage of IL-17 in tumor tissue contributed to suppressing tumor growth via the inhibition of angiogenesis as well as CTL activation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 388. doi:10.1158/1538-7445.AM2011-388