Article: article from journal or magazin.
Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy.
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
In spite of their having sufficient immunogenicity, tumor vaccines remain largely ineffective. The mechanisms underlying this lack of efficacy are still unclear. Here we report a previously undescribed mechanism by which the tumor endothelium prevents T cell homing and hinders tumor immunotherapy. Transcriptional profiling of microdissected tumor endothelial cells from human ovarian cancers revealed genes associated with the absence or presence of tumor-infiltrating lymphocytes (TILs). Overexpression of the endothelin B receptor (ET(B)R) was associated with the absence of TILs and short patient survival time. The ET(B)R inhibitor BQ-788 increased T cell adhesion to human endothelium in vitro, an effect countered by intercellular adhesion molecule-1 (ICAM-1) blockade or treatment with NO donors. In mice, ET(B)R neutralization by BQ-788 increased T cell homing to tumors; this homing required ICAM-1 and enabled tumor response to otherwise ineffective immunotherapy in vivo without changes in systemic antitumor immune response. These findings highlight a molecular mechanism with the potential to be pharmacologically manipulated to enhance the efficacy of tumor immunotherapy in humans.
Animals, Antigens, CD3/biosynthesis, Cell Adhesion, Cell Line, Tumor, Endothelium/embryology, Endothelium/metabolism, Female, Gene Expression Profiling, Humans, Immune System, Immunotherapy/methods, Intercellular Adhesion Molecule-1/metabolism, Mice, Mice, Inbred C57BL, Neoplasms/immunology, Receptor, Endothelin B/metabolism, Receptor, Endothelin B/physiology, T-Lymphocytes/metabolism
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