How beta-catenin expands Foxp3+RORgammat+ Pro-inflammatory T-regulatory cells

描述(申请人提供)：我们的初步工作已经确定，调节性T细胞(Treg)在结肠癌的病理学中有两个方面：一个是抑制炎症和保护作用，另一个是促炎和促进肿瘤。Tregs促炎亚群的优先扩张促进了肿瘤的发生和肠道病理。促炎性树突状细胞不同于经典的树突状细胞，因为它们能激活�-连环蛋白并表达�-连环蛋白的转录靶点、TH17细胞的标志性转录因子ROR？T。我们已经证明，促炎性Tregs表达ROR？T与结肠炎和息肉病的发生有关。我们还表明，通过靶向激活Treg中的�-catenin，可以产生促炎Treg，这会导致结肠炎和结肠癌。我们有证据表明，ROR？T的表达是通过提高染色质的可及性来促进的。与这一发现一致的是，胸腺细胞中�-连环蛋白的激活增强了其伴侣Tcf-1结合位点附近染色质的可及性，并促进了淋巴转录因子向这些位点的募集。这些染色质变化与一组定义促炎Tregs的炎症相关基因(包括RoR？T)的激活有关。基于这些观察，我们假设�-连环蛋白在Treg中的激活启动了一个由染色质景观和基因表达变化驱动的促炎和促肿瘤计划。为了验证这一假设，我们将解决以下假设：1)�-catenin通过启动表观遗传学和基因表达变化在Treg中协调促炎程序，2)�-catenin是产生促炎Treg所必需的，3)Wnt/�-catenin/Tcf-1通路是治疗人类结肠癌的可行靶点。结肠肿瘤中Tregs的积聚与不良和良好的临床结果都有关。阐明区分病理性和保护性Tregs的性质和机制将为在癌症治疗中针对有害亚群提供工具。因此，拟议研究的结果可能重新定义我们目前对Treg功能和免疫干预在结肠癌中的理解。此外，拟议的研究将阐明Wnt/�-catenin/Tcf-1途径的基本作用机制。

DESCRIPTION (provided by applicant): 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.