Role of S.aureus in Cutaneous T Cell Lymphoma Pathogenesis

摘要 皮肤T细胞淋巴瘤(CTCL)是一组与血液相关的异质性癌症，其特征是 通过慢性炎症和皮肤中恶性T细胞的积聚。在淋巴瘤中，CTCL是 独特的以转化细胞显著的真皮趋向性为特征的-接触微生物可能 对疾病病因学有贡献。CTCL患者常死于细菌感染，且两者之间存在相关性 观察到某些金黄色葡萄球菌菌株的存在和疾病的严重程度。 共生菌和病原菌可影响幼稚T淋巴细胞的分化，引发增殖 和通过产生超抗原(SAG)激活T细胞，并产生允许的 影响趋化因子和细胞因子表达对肿瘤细胞微环境的影响。我们假设， 以及个体的遗传易感性和T细胞或T淋巴细胞获得的突变 前体、接触金黄色葡萄球菌和某些菌株产生的下垂促进恶性 CTCL的转化和克隆进化。 其他小组先前的研究和我们的初步研究表明，金黄色葡萄球菌与CTCL有关 发病机制。我们将从CTCL患者的皮肤中分离、测序和研究金黄色葡萄球菌。 肿瘤部位和未受影响的皮肤)，并确定这些菌株产生的毒素和下垂的谱系。 我们预计，与CTCL相关的菌株在产生大量SAG的能力上将有所不同 每种生物体的类型及其SAG基因含量的分布。我们将使用体外方法来评估如何 CTCL患者皮肤微生物区系产生的SAGS等毒素和外源蛋白对T细胞的贡献 活化、增殖和恶变。 为进一步了解金黄色葡萄球菌在CTCL发病机制中的作用并论证其病因。 金黄色葡萄球菌定植与恶性疾病之间的联系，我们将使用我们的新的CTCL动物模型 和我们的无菌设施，以检查微生物暴露对CTCL启动和进展的影响。我们 还将利用尖端、单电池、高通量技术，实现同时 分析表面表位，T细胞受体基因重排，并实现转录 CTCL中肿瘤微环境的前所未有的分辨率，并检查在 微环境对金黄色葡萄球菌定植的影响。 我们建议中概述的研究将为CTCL的发病机制提供重要的见解，并将 开发比目前的化疗更有针对性和毒性更低的未来疗法 接近了。

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.