title: Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy.
abstract: 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.
authors.affiliation: Center for Research on Ovarian Cancer Early Detection and Cure, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Buckanovich
authors.forename: Andrea
authors.initials: A
authors.lastname: Facciabene
authors.forename: Sarah
authors.initials: S
authors.lastname: Kim
authors.forename: Fabian
authors.initials: F
authors.lastname: Benencia
authors.forename: Dimitra
authors.initials: D
authors.lastname: Sasaroli
authors.forename: Klara
authors.initials: K
authors.lastname: Balint
authors.forename: Dionysios
authors.initials: D
authors.lastname: Katsaros
authors.forename: Anne
authors.initials: A
authors.lastname: O'Brien-Jenkins
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Gimotty
authors.forename: George
authors.initials: G
authors.lastname: Coukos
mesh_terms: 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*
chemical_list: D017252:CD3 Complex; D044023:Receptor, Endothelin B; D018799:Intercellular Adhesion Molecule-1