Article abstract
Nature Medicine 14, 28 - 36 (2008)
Published online: 6 January 2008 | doi:10.1038/nm1699
Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy
Ronald J Buckanovich1,2,7,8, Andrea Facciabene1,8, Sarah Kim1, Fabian Benencia1,3, Dimitra Sasaroli1,4, Klara Balint1, Dionysios Katsaros6, Anne O'Brien-Jenkins1, Phyllis A Gimotty1,5 & George Coukos1,3
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.
- Center for Research on Ovarian Cancer Early Detection and Cure, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
- Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
- Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis 68100, Greece.
- Department of Obstetrics and Gynecology, University of Turin, Torino 10126, Italy.
- Current address: Department of Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
- These authors contributed equally to this work.
Correspondence to: George Coukos1,3 e-mail: gcks@mail.med.upenn.edu
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