# Reduced vascular leakage correlates with breast carcinoma T regulatory cell infiltration but not with metastatic propensity

## TL;DR

Reduced vascular leakage in breast cancer is linked to immune suppression and larger tumors but not increased metastasis.

## Contribution

A mouse model and human cohort study reveal how vascular normalization affects immune cell infiltration and tumor progression.

## Key findings

- Low vascular leakage correlates with increased regulatory T cell infiltration in human breast tumors.
- Vascular normalization reduces tumor metastasis and alters immune checkpoint gene expression in immune cells.
- Reduced vascular leakage is not associated with increased metastatic potential in breast cancer.

## Abstract

The vasculature and the immune system both play roles in breast cancer progression and metastasis. In an experimental mouse model of Shb‐gene deficiency in endothelial cells, breast cancer lung metastasis correlated with immune suppression rather than with vascular leakage. The present study aimed to assess underlying gene expression changes in endothelial and immune cells responsible for this phenotype and to explore their relationship to human disease. Mouse endothelial cell Shb‐gene deficiency, leading to ‘vessel normalization’, resulted in altered expression of chemo/cytokine genes and upregulation of immune checkpoint genes in immune cells. Endothelial cells under these conditions exhibited gene expression patterns compatible with reduced angiogenesis and vascular leakage. Additionally, genes whose products relate to immune cell vascular transmigration and function were affected. In a human triple‐negative breast cancer cohort, tumors with reduced vascular leakage exhibited a higher relative proportion of regulatory T cells and larger tumor size. However, these changes were not associated with increased metastasis. In conclusion, a low leakage vascular phenotype reduces tumor cell intravasation/metastasis and modifies the immune response, which in the current context becomes pro‐tumoral.

A mouse model for vascular normalization and a human breast cancer cohort were studied to understand the relationship between vascular leakage and tumor immune suppression. For this, endothelial and immune cell RNAseq, staining for vascular function, and immune cell profiling were employed. The data reveal that low leakage correlated with stronger tumor immune suppression.