The malignant microenvironment in early cutaneous T-cell lymphoma

项目总结/摘要 皮肤微环境如何促进恶性CD4 + T细胞的增殖 皮肤T细胞淋巴瘤（CTCL）还没有被很好地理解。我们和其他人表明， 免疫抑制性巨噬细胞存在于CTCL损伤皮肤中并表达Toll 与受体-4（TLR4）一样，通过其信号传导改变巨噬细胞表型， 功能我们还发现，纤维连接蛋白，皮肤细胞外基质的主要成分， (ECM)在CTCL皮肤中以选择性剪接的形式异常表达 同种型EDA，TLR4的配体。在这里，我们使用优化的免疫能力的小鼠 CTCL模型，研究恶性CTCL微环境。我们建议调查 这是两个相互关联的目标。1)确定TLR4-EDA通路在 2）确定TLR4-EDA信号传导对CTCL肿瘤生长的影响。 巨噬细胞表型和功能。这项工作将提供宝贵的信息， CTCL中ECM失调和肿瘤免疫抑制之间相互作用， 增进对巨噬细胞介导免疫抑制的一般理解。

Project Summary/Abstract How the skin microenvironment contributes to proliferation of malignant CD4+ T cells in cutaneous T-cell lymphoma (CTCL) is not well understood. We and others show that immunosuppressive macrophages are present in CTCL lesional skin and express Toll Like Receptor-4 (TLR4), signaling through which modifies macrophage phenotype and function. We also find that fibronectin, a major component of the skin extracellular matrix (ECM) is aberrantly expressed in CTCL skin in the form of an alternatively spliced isoform EDA, a ligand for TLR4. Here we use an optimized immune competent murine model for CTCL to study malignant CTCL microenvironment. We propose to investigate two interrelated aims in this setting. 1) Determine the role of the TLR4-EDA pathway on CTCL tumor growth and 2) Determine the impact of TLR4-EDA signaling on macrophage phenotype and function. This work will provide valuable information on the interplay between ECM dysregulation and tumor immunosuppression in CTCL and may improve understanding of macrophage mediated immune suppression in general.