Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immun
Author: ["Ronald J Buckanovich","Andrea Facciabene","Sarah Kim","Fabian Benencia","Dimitra Sasaroli","Klara Balint","Dionysios Katsaros","Anne O'Brien-Jenkins","Phyllis A Gimotty","George Coukos"]
Publication: Nature Medicine
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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 (ETBR) was associated with the absence of TILs and short patient survival time. The ETBR 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, ETBR 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.
Cite this article
Buckanovich, R., Facciabene, A., Kim, S. et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat Med 14, 28–36 (2008). https://doi.org/10.1038/nm1699
