Journal
NATURE MEDICINE
Volume 14, Issue 1, Pages 28-36Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm1699
Keywords
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Funding
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [K12HD043459] Funding Source: NIH RePORTER
- FOGARTY INTERNATIONAL CENTER [D43TW000671] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [R01CA112162, P50CA083638, R01CA098951] Funding Source: NIH RePORTER
- FIC NIH HHS [D43-TW00671] Funding Source: Medline
- NCI NIH HHS [R01-CA112162, P50-CA083638, R01-CA098951] Funding Source: Medline
- NICHD NIH HHS [K12-HD43459] Funding Source: Medline
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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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