Abstract 5324: Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis

Abstract

The intestinal tract is subject to constant stimulation of immune cells and intestinal epithelial cells either by noninfectious antigens or infection. Recent studies identified the role of IL-17A in chronic inflammation in intestinal epithelium. Yet the intrinsic role of endogenous IL-17A in spontaneous intestinal tumorigenesis has not been addressed previously. Ablation of IL-17A significantly reduced tumor development in mice bearing a heterozygote mutation in the APC (adenomatous polyposis coli) gene (ApcMin/+ mice). There was a marked decrease in IL-6 and IL-23 (p19), as well as a decrease in IL-1β, suggesting that the inflammatory microenvironment was significantly changed by ablating IL-17A. We also found a significant decrease in CD44 and proinflammatory mediators such as KC (Keratinocyte Chemoattractant) and Cox-2. There was also a reduced infiltration of lymphocytes including T cells and preservation of intestinal architecture and the presence of APC protein in intestinal epithelial cells in IL-17AKO ApcMin/+ mice. Interestingly, IL-17A ablation also corrected immunological abnormalities such as splenomegaly and thymic atrophy in ApcMin/+ mice. We tested whether CD4 T cells from ApcMin/+ mice are more proliferative based on its role as a tumor suppressor gene, thereby regulating cell cycle. We observed that CD4 T cells from ApcMin/+ mice were hyperproliferative when compared with their wildtype littermate controls upon TcR (T cell receptor) stimulation. This hyperproliferation was more obvious following stronger stimulation through the TcR. Next, we tested whether the effector CD4 T cells are more refractory to regulatory T cell (Treg)-mediated suppression. Upon co-culture with wildtype Treg cells, ApcMin/+ CD4 effector T cells were more resistant to Treg-mediated suppression especially at a high ratio of effectors to Treg, suggesting that the suppression on ApcMin/+ CD4 effector T cells are not as efficient as for wildtype CD4 effector T cells. Finally, these CD4 T cells from ApcMin/+ mice induced colitis in immunodeficient mice upon adoptive transfer, while the ablation of IL-17A in CD4 T cells in ApcMin/+ mice (IL-17A KO ApcMin/+ mice) completely abolished this pathogenic potential in vivo, clearly showing that ablation of IL-17A abrogated hyperproliferation and colitogenic potential in immunodeficient mice. This was consistent with our observation of the phenotypic changes in intestinal tumorigenesis. Taken together, our results suggest an important proinflammatory role of IL-17A and its correction of immune abnormalities in spontaneous intestinal tumorigenesis. We demonstrate altered CD4 T cell functions from ApcMin/+ mice which favors intestinal tumorigenesis and the ablation of IL-17A can abolish these altered function, suggesting the importance of T-cell mediated IL-17A in spontaneous intestinal tumorigenesis Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5324.

NKG2D signaling regulates IL-17A-producing γδT cells to promote cancer progression

“…IL-17A, a pro-inflammatory cytokine known to drive intestinal tumorigenesis in the Apc min/+ mouse model (Chae et al, 2010), is produced by γδT cells. Thus, we hypothesized that NKG2D regulates IL-17A expression, thereby contributing to the inflammatory milieu and tumor progression.…”