| First Author | Buckanovich RJ | Year | 2008 |
| Journal | Nat Med | Volume | 14 |
| Issue | 1 | Pages | 28-36 |
| PubMed ID | 18157142 | Mgi Jnum | J:130885 |
| Mgi Id | MGI:3772506 | Doi | 10.1038/nm1699 |
| Citation | Buckanovich RJ, et al. (2008) Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat Med 14(1):28-36 |
| abstractText | 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 (ET(B)R) was associated with the absence of TILs and short patient survival time. The ET(B)R 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, ET(B)R 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. |
