STAT3: At the Crossroads of Inflammation and Cancer

描述(由申请人提供)：在几种人类癌症中观察到信号转导和转录激活因子3(STAT3)的结构性活性，反映了该转录因子在调节细胞凋亡和增殖中的重要性。STAT3是Th17细胞分化所必需的，Th17细胞是CD4+辅助T细胞的一个亚群，产生促炎细胞因子IL-17，并与各种炎症疾病有关。研究表明，皮肤T细胞淋巴瘤(CTCL)患者分离的T淋巴细胞具有结构性的STAT3激活和IL-17产生，CTCL是一种恶性T细胞迁移到皮肤的疾病。这些发现表明，STAT3驱动的Th17细胞分化可能在CTCL和其他T细胞恶性肿瘤的发病机制中发挥作用。为了研究STAT3在T细胞转化中的作用，建立了一种新的转基因小鼠模型，在该模型中，CD4-CRE诱导T细胞特异性表达高活性突变体STAT3(STAT3C)。在6个月大的时候，100%的CD4-CRE R26STAT3Cstopfl/+小鼠患上了一种淋巴增殖性疾病，非常类似于CTCL。在可见的皮肤病理出现之前，小鼠的淋巴结和皮肤中的Th17细胞水平已经增加，这表明Th17驱动的低度炎症有助于疾病的发展。该项目的目的是研究持续的慢性炎症在T细胞恶性转化中的作用，并揭示在细胞转化过程中积累的STAT3信号通路中可逆的表观遗传学变化。临床上批准使用的一种有效的CTCL治疗方法是使用组蛋白脱乙酰酶(HDAC)抑制剂，这表明乙酰化的变化可能有助于CTCL的发病，已发表的观察表明HDAC抑制剂可能调节STAT3的转录活性。所描述的CTCL的STAT3C小鼠模型将被用来检测STAT3驱动的促炎Th17细胞分化对CTCL病理的贡献，并在这种疾病的背景下研究HDAC抑制剂对效应T细胞分化的影响。拟议的实验将揭示Th17驱动的促炎微环境在CTCL和其他淋巴瘤发展中的作用，并将探索T细胞在转化过程中发生的染色质变化，可能产生治疗淋巴系统恶性肿瘤的新药物靶点。 公共卫生相关性：拟议的项目在免疫学和癌症治疗领域具有重大影响，有可能改善淋巴瘤患者的治疗选择和生活质量。这项工作旨在研究慢性炎症在皮肤T细胞淋巴瘤(CTCL)这种衰弱疾病的发展中所起的作用。这项研究将检测炎性T细胞在CTCL病理中的作用，并揭示免疫细胞信号通路的可逆变化，这些变化可能成为未来CTCL新疗法和诊断策略的靶点。

DESCRIPTION (provided by applicant): Constitutive activity of signal transducer and activator of transcription 3 (STAT3) is observed in several human cancers, reflecting the importance of this transcription factor in the regulation of apoptosis and proliferation. STAT3 is required for te differentiation of Th17 cells, a subset of CD4+ helper T cells that produces the proinflammatory cytokine IL-17 and has been implicated in various inflammatory disorders. Studies have shown constitutive STAT3 activation and IL-17 production in T lymphocytes isolated from patients with cutaneous T cell lymphoma (CTCL), a disease in which malignant T cells migrate to the skin. These findings indicate that STAT3-driven Th17 cell differentiation may play a role in the pathogenesis of CTCL and other T cell malignancies. To examine the role of STAT3 in T cell transformation, a novel transgenic mouse model was developed in which CD4-Cre induces expression of a hyperactive mutant STAT3 (STAT3C) specifically in T cells. By six months of age, 100% of CD4-Cre R26STAT3Cstopfl/+ mice develop a lymphoproliferative disease highly reminiscent of CTCL. The mice have increased levels of Th17 cells in the lymph nodes and skin before visible skin pathology is present, suggesting that Th17-driven low-grade inflammation contributes to the development of the disease. The aims of this project are to examine the role of sustained chronic inflammation in the malignant transformation of T cells and to uncover reversible epigenetic changes in the STAT3 signaling pathway that accumulate during cellular transformation. An effective CTCL therapy approved for use in the clinic is the use of histone deacetylase (HDAC) inhibitors, suggesting that changes in acetylation may contribute to the pathogenesis of CTCL, and published observations indicate that HDAC inhibitors may modulate the transcriptional activity of STAT3. The described STAT3C mouse model of CTCL will be used to examine the contribution of STAT3-driven differentiation of proinflammatory Th17 cells to CTCL pathology and to investigate the effects of HDAC inhibitors on effector T cell differentiation in the context of this disease. The proposed experiments will reveal the role of a Th17-driven proinflammatory microenvironment in the development of CTCL and other lymphomas and will probe the chromatin changes that occur in T cells during transformation, potentially yielding novel drug targets for the treatment of lymphoid malignancies. PUBLIC HEALTH RELEVANCE: The proposed project has significant implications in the fields of immunology and cancer therapy, potentially improving the treatment options and quality of life for patients with lymphoma. The work is intended to examine the role of chronic inflammation in the development of the debilitating disease, cutaneous T cell lymphoma (CTCL). This research will examine the contribution of inflammatory T cells to CTCL pathology, as well as uncover reversible changes in immune cell signaling pathways that may serve as future targets for novel CTCL therapies and diagnostic strategies.