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

描述（由申请人提供）：我们的初步工作已经确定调节性t细胞（Tregs）在结肠癌的病理中有两个方面：一个是抑制炎症和保护性的，另一个是促炎和促肿瘤的。促炎性Tregs亚群的优先扩张促进肿瘤发生和肠道病理。促炎treg与传统treg不同，因为它们激活了catenin并表达ROR？t是TH17细胞的标志性转录因子，也是¿-catenin的转录靶点。我们已经展示了ROR的表达式？促炎Tregs产生的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，从而导致结肠炎和结肠癌。我们有证据表明，ROR？通过增强染色质可及性促进T。与这一发现一致，胸腺细胞中¿-catenin的激活增强了与其伴侣Tcf-1结合的DNA位点附近染色质的可及性，并促进了淋巴转录因子在这些位点的募集。这些染色质变化与一组炎症相关基因(包括ROR？t)定义促炎Tregs。基于这些观察结果，我们假设Tregs中的¿-catenin激活启动了由染色质景观和基因表达变化驱动的促炎和促肿瘤程序。为了验证这一假设，我们将解决以下假设：1)¿-catenin通过启动表观遗传和基因表达变化来协调treg中的促炎程序，2)¿-catenin是促炎treg产生所必需的，3)Wnt/¿-catenin/Tcf-1途径是治疗人类结肠癌的可行治疗靶点。结肠肿瘤中Tregs的积累与不良和良好的临床结果有关。阐明区分病理性treg和保护性treg的特性和机制将为癌症治疗中特异性靶向有害亚群提供工具。因此，这些研究的发现可能会重新定义我们目前对Treg功能和结肠癌免疫干预的理解。此外，所提出的研究将阐明Wnt/¿-catenin/Tcf-1通路的基本作用机制。

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.