Our preliminary work has established that regulatory T-cells (Tregs) have two faces in the pathology of colon cancer: one that suppresses inflammation and is protective, and another that is pro-inflammatory and tumor promoting. Preferential expansion of a pro-inflammatory subset of Tregs promotes oncogenesis and intestinal pathology. Pro-inflammatory Tregs are distinct from classical Tregs because they have activated ?-catenin and express ROR?t, the signature transcription factor of TH17 cells and a transcriptional target of ?-catenin. We have shown that expression of ROR?t by pro-inflammatory Tregs is linked to the development of colitis and polyposis. We have also shown that pro-inflammatory Tregs can be generated through targeted activation of ?-catenin in Tregs, and that this results in colitis and colon cancer. We have evidence to suggest that expression of ROR?t is facilitated through enhanced chromatin accessibility. Consistent with this finding, activation of ?-catenin in thymocytes enhances chromatin accessibility near DNA sites bound by its partner Tcf-1, and facilitates the recruitment of lymphoid transcription factors to these sites These chromatin changes were associated with activation of a group of inflammation-associated genes (including ROR?t) that define pro-inflammatory Tregs. Based on these observations, we hypothesize that ?-catenin activation in Tregs initiates a pro-inflammatory and tumor promoting program driven by changes in chromatin landscape and gene expression. To test this hypothesis, we will address the following postulates: 1) ?-catenin orchestrates a pro-inflammatory program in Tregs by initiating epigenetic and gene expression changes, 2) ?-catenin is required for the generation of pro-inflammatory Tregs, 3) the Wnt/?-catenin/Tcf-1 pathway is a viable therapeutic target for the treatment of human colon cancer. Accumulation of Tregs in colonic tumors has been linked with both poor and favorable clinical outcomes. Elucidating the properties and mechanisms that distinguish pathological from protective Tregs will provide the tools to specifically target the harmful subsets in cancer therapy. Therefore, findings from the proposed studies could redefine our current understanding of Treg function and immune intervention in colon cancer. Furthermore the proposed studies will elucidate fundamental mechanisms of action of the Wnt/?-catenin/Tcf-1 pathway.
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