The VE-Cadherin/β-catenin signalling axis regulates immune cell infiltration into tumours

Yang Zhao, Jia Li, Ka Ka Ting, Jinbiao Chen, Paul Coleman, Ken Liu, Li Wan, Thorleif Moller, Mathew A. Vadas, Jennifer R. Gamble

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Abstract

Vascular normalisation, the process that reverses the structural and functional abnormalities seen in tumour-associated vessels, is also accompanied by changes in leucocyte trafficking. Our previous studies have shown the normalisation effects of the agent CD5-2 which acts to stabilise VE-Cadherin leading to increased penetration of CD8 + T cells but decreased infiltration of neutrophils (CD11b +Gr1hi) into tumour parenchyma. In the present study, we demonstrate that VE-Cadherin stabilisation through CD5-2 treatment of purified endothelial cells (ECs) results in a similar leucocyte-selective regulation of transmigration, suggesting the existence of an endothelial specific intrinsic mechanism. Further, we show by RNA sequencing (RNA-seq)-based transcriptomic analysis, that treatment of ECs with CD5-2 regulates chemokines known to be involved in leucocyte transmigration, including upregulation of CCL2 and CXCL10 that facilitate CD8 + T cell transmigration. Both in vitro and in vivo mechanistic studies revealed that the increased CCL2 expression was dependent on expression of VE-Cadherin and downstream activation of the AKT/GSK3β/β-catenin/TCF4 signalling pathway. CD5-2 treatment also contributed to the reorganisation of the cytoskeleton, inducing reorganisation of stress fibres to circumferential actin, which previously has been described as associated with the stabilisation of the endothelial barrier, and amplification of the transcellular migration of CD8 + T cells. Thus, we propose that promotion of endothelial junctional integrity during vascular normalisation not only inhibits vascular leak but also resets the endothelial dependent regulation of immune cell infiltration.

Original languageEnglish
Pages (from-to)1-15
Number of pages15
JournalCancer Letters
Volume496
DOIs
Publication statusPublished - 1 Jan 2021
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • CD8+ T cell infiltration
  • Normalisation
  • Transcellular migration
  • VE-Cadherin
  • β-catenin

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