Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy.
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.
D000818:Animals; D017252:CD3 Complex / Q000096:biosynthesis; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004727:Endothelium / Q000196:embryology / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007107:Immune System; D007167:Immunotherapy / Q000379:methods*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology; D044023:Receptor, Endothelin B / Q000378:metabolism / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism*
D017252:CD3 Complex; D044023:Receptor, Endothelin B; D018799:Intercellular Adhesion Molecule-1