Targeting vascular endothelial-cadherin in tumor-associated blood vessels promotes T-cell-mediated immunotherapy

Yang Zhao, Ka Ka Ting, Jia Li, Victoria C. Cogger, Jinbiao Chen, Anna Johansson-Percival, Shin Foong Ngiow, Jeff Holst, Georges Grau, Shom Goel, Thorleif Muller, Elisabetta Dejana, Geoff McCaughan, Mark J. Smyth, Ruth Ganss, Mathew A. Vadas, Jennifer R. Gamble

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

T-cell infiltration of solid tumors is associated with improved prognosis and favorable responses to immunotherapy. Mechanisms that enable tumor infiltration of CD8+ T cells have not been defined, nor have drugs that assist this process been discovered. Here we address these issues with a focus on VE-cadherin, a major endothelial cell-specific junctional protein that controls vascular integrity. A decrease in VE-cadherin expression is associated with tumor pathology. We developed an oligonucleotide-based inhibitor (CD5-2), which disrupted the interaction of VE-cadherin with its regulator miR-27a, resulting in increased VE-cadherin expression. Administration of CD5-2 in tumor-bearing mice enhanced expression of VE-cadherin in tumor endothelium, activating TIE-2 and tight junction pathways and normalizing vessel structure and function. CD5-2 administration also enhanced tumor-specific T-cell infiltration and spatially redistributed CD8+ T cells within the tumor parenchyma. Finally, CD5-2 treatment enhanced the efficacy of anti-PD-1 blocking antibody. Our work establishes a role for VE-cadherin in T-cell infiltration in tumors and offers a preclinical proof of concept for CD5-2 as a therapeutic modifier of cancer immunotherapy via effects on the tumor vasculature.

Original languageEnglish
Pages (from-to)4434-4447
Number of pages14
JournalCancer Research
Volume77
Issue number16
DOIs
Publication statusPublished - 15 Aug 2017
Externally publishedYes

Bibliographical note

A correction exists for this article and has been included in the current online and pdf versions.

Keywords

  • Animals
  • Cadherins/immunology
  • Colonic Neoplasms/blood supply
  • Endothelium, Vascular/immunology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Immunotherapy/methods
  • Melanoma, Experimental/blood supply
  • Mice
  • Molecular Targeted Therapy
  • T-Lymphocytes/immunology

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