Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy

RJ Buckanovich, A Facciabene, S Kim, F Benencia… - Nature medicine, 2008 - nature.com
RJ Buckanovich, A Facciabene, S Kim, F Benencia, D Sasaroli, K Balint, D Katsaros…
Nature medicine, 2008nature.com
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) …
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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