Endothelin B Receptor Mediates the Endothelial Barrier to T Cell Homing to Tumors and Disables Immune Therapy

Nat Med. 2008 Jan;14(1):28-36. doi: 10.1038/nm1699. Epub 2008 Jan 6.

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 (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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD3 Complex / biosynthesis
  • Cell Adhesion
  • Cell Line, Tumor
  • Endothelium / embryology
  • Endothelium / metabolism
  • Female
  • Gene Expression Profiling
  • Humans
  • Immune System
  • Immunotherapy / methods*
  • Intercellular Adhesion Molecule-1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms / immunology
  • Receptor, Endothelin B / metabolism
  • Receptor, Endothelin B / physiology*
  • T-Lymphocytes / metabolism*

Substances

  • CD3 Complex
  • Receptor, Endothelin B
  • Intercellular Adhesion Molecule-1