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

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/GSK3 beta/beta-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.

Automated summary

The stabilization of VE-Cadherin through CD5-2 treatment selectively regulates leukocyte transmigration, promoting the penetration of CD8(+) T cells while reducing the infiltration of neutrophils. This effect is mediated in part through the upregulation of chemokines like CCL2 and CXCL10, which facilitate immune cell transmigration, and involves the activation of the AKT/GSK3 beta/beta-catenin/TCF4 signaling pathway. Additionally, CD5-2 treatment induces cytoskeletal reorganization and promotes the transcellular migration of CD8(+) T cells by stabilizing the endothelial barrier.