Research Project
10290730
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.
