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

Author & Article Information

  • Authors: Ronald J Buckanovich, Andrea Facciabene, Sarah Kim, Fabian Benencia, Dimitra Sasaroli, Klara Balint, Dionysios Katsaros, Anne O'Brien-Jenkins, Phyllis A Gimotty & George Coukos

  • Nature Medicine volume 14, pages28–36


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.


See the original article here | Nature Medicine

Previous
Previous

Intercellular adhesion molecule-1-dependent stable interactions between T cells and dendritic cells determine CD8+ T cell memory

Next
Next

Tumor blood vessels, a difficult hurdle for infiltrating leukocytes