Role of S.aureus in Cutaneous T Cell Lymphoma Pathogenesis

摘要 皮肤T细胞淋巴瘤（CTCL）是一组异质性血液相关癌症，其特征在于 慢性炎症和恶性T细胞在皮肤中的积累。在淋巴瘤中，CTCL是 其独特的特征是转化细胞的显著的皮肤向性，在那里暴露于微生物可能 有助于疾病病因。CTCL患者经常死于细菌感染， 已经观察到某些金黄色葡萄球菌菌株的存在和疾病的严重性。 共生菌和致病菌可影响幼稚T淋巴细胞的分化，触发增殖 通过产生超抗原（SAgs）激活T细胞，并产生一个允许的 通过影响趋化因子和细胞因子的表达来调节肿瘤细胞的微环境。我们假设， 沿着个体的遗传倾向和T细胞或T淋巴细胞获得的突变 前体，暴露于S.由这种致病菌的某些菌株产生的金黄色葡萄球菌和SAgs促进恶性肿瘤的发生。 转化和克隆进化。 其他小组先前的研究和我们的初步研究表明S。CTCL中特异性金黄色葡萄球菌 发病机制我们将分离、测序和研究S。从CTCL患者的皮肤分离的金黄色葡萄球菌（来自 肿瘤部位和未受影响的皮肤），并确定由这些菌株产生的毒素和SAg的库。 我们预计CTCL相关分离株在产生大量SAg的能力和产生大量SAg的能力上都不同， 每种生物的类型及其SAg基因含量的分布。我们将使用体外方法来评估 由CTCL患者的皮肤微生物群产生的SAgs和其他毒素和外蛋白有助于T细胞增殖。 活化、增殖和恶性转化。 为了进一步了解S.金黄色葡萄球菌CTCL发病机制，并证明因果关系 S之间的联系。金黄色葡萄球菌定植和恶性疾病，我们将使用我们新的CTCL动物模型 和我们的无菌设施，以检查微生物暴露对CTCL发生和进展的影响。我们 还将利用尖端的单细胞高通量技术， 分析表面表位、T细胞受体基因重排和转录组学， CTCL中肿瘤微环境的前所未有的分辨率，并检查 微环境对S.金黄色葡萄球菌定植。 我们提案中概述的研究将为CTCL发病机制提供重要的见解，并将为我们提供信息。 开发比当前化疗更有针对性且毒性更低的未来疗法 接近。

Abstract Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of blood-related cancers characterized by chronic inflammation and accumulation of malignant T cells in the skin. Among lymphomas, CTCL is uniquely characterized by the striking dermal tropism of transformed cells—where exposure to microbes might contribute to disease etiology. CTCL patients often succumb to bacterial infections, and a correlation between the presence of certain strains of Staphylococcus aureus and disease severity has been observed. Commensal and pathogenic bacteria can influence differentiation of naïve T lymphocytes, trigger proliferation and activation of T cells through production of superantigens (SAgs), and create a permissive microenvironment for tumor cells by influencing chemokine and cytokine expression. We hypothesize that, along with genetic predisposition of an individual and mutations acquired by T cells or T lymphocyte precursors, exposure to S. aureus and SAgs produced by some strains of this pathobiont promotes malignant transformation and clonal evolution in CTCL. Prior research by other groups and our preliminary studies implicate S. aureus specifically in CTCL pathogenesis. We will isolate, sequence and study S. aureus isolates from the skin of CTCL patients (from tumor sites and unaffected skin) and determine the repertoire of toxins and SAgs produced by these strains. We anticipate that CTCL-associated isolates will differ in both the ability to produce large numbers of SAg types per organism and the distribution of their SAg gene content. We will use in vitro methods to evaluate how SAgs and other toxins and exoproteins produced by skin microbiota of CTCL patients contribute to T cell activation, proliferation, and malignant transformation. To further understand the contribution of S. aureus to CTCL pathogenesis and to demonstrate a causal connection between S. aureus colonization and malignant disease, we will use our new animal model of CTCL and our germ-free facility to examine the impact of microbial exposure on CTCL initiation and progression. We will also take advantage of cutting-edge, single-cell, high-throughput technology that enables simultaneous analysis of surface epitopes, T cell receptor gene rearrangements, and transcriptomics to achieve unprecedented resolution of the tumor microenvironment in CTCL and to examine changes in the microenvironment upon S. aureus colonization. The studies outlined in our proposal will provide significant insight into CTCL pathogenesis and will inform development of future therapies that are more targeted and less toxic than current chemotherapeutic approaches.