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.
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Acknowledgements
pcDNA3.1-LLO-E7 vector was kindly provided by Y. Paterson (University of Pennsylvania). This work was supported by NIH grants R01-CA098951, P50-CA083638 Ovarian Cancer SPORE and R01-CA112162. A.F. was supported by the US National Ovarian Cancer Coalition. R.J.B. was supported by an NIH–National Institute of Child Health and Human Development grant (K12-HD43459 Career Development in Interdisciplinary Women's Health Research) and the Ovarian Cancer Research Fund. F.B. was supported by NIH grant D43-TW00671 and the Fogarty International Center. The Laser Capture Microdissection facility was supported by a generous grant from the Fannie Rippel Foundation.
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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
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DOI: https://doi.org/10.1038/nm1699
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