The malignant microenvironment in early cutaneous T-cell lymphoma

项目摘要/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)目前还没有很好的认识。我们和其他人证明了 CTCL皮损中存在免疫抑制巨噬细胞并表达Toll 类似受体-4(TLR4)，通过信号调节巨噬细胞表型和 功能。我们还发现，纤维连接蛋白是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 异构体EDA，TLR4的配体。在这里我们使用了一种免疫能力优化的小鼠 研究恶性CTCL微环境的CTCL模型我们建议调查 在这个背景下有两个相互关联的目标。1)确定TLR4-EDA通路在 TLR4-EDA信号转导通路对CTCL肿瘤生长的影响 巨噬细胞的表型和功能。这项工作将提供有价值的信息 CTCL中细胞外基质调节异常与肿瘤免疫抑制的相互作用 从总体上提高对巨噬细胞介导的免疫抑制的理解。

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.