Peritumoral venular endothelial cells modulate T cell infiltration into solid tumors 4763

Abstract Description Effective T cell immunity against solid tumors requires not only functional capacity but also targeted trafficking to tumor sites. Effector T cells must engage in a multi-step adhesion process with endothelial cells (ECs) to extravasate from the bloodstream into tissues. While these interactions are well-characterized in venular endothelial cells (VECs) of benign tissues, they remain poorly understood in malignant tumors. Tumor vasculature is known for its irregular morphology and disrupted organization. Using single-cell RNA-seq and spatial transcriptomics, we show that some tumor ECs still maintain a venular transcriptional profile. Intratumoral VECs exhibit an immature phenotype with reduced adhesion molecule expression, whereas marginal VECs are activated and closely associated with infiltrating T cells. Employing atypical chemokine receptor 1 (ACKR1) as a novel VEC marker, we find that VECs are enriched in ‘hot’ tumors with high T cell infiltration but are depleted in ‘cold’ tumors with low infiltration. This trend is observed across heterotopic and orthotopic murine models and human samples. Notably, ACKR1+ VECs predominantly localize at tumor margins, corresponding to sites where adoptively transferred T cells preferentially home, suggesting that efficient T cell infiltration relies on these VECs. These findings highlight that peritumoral VEC abundance and functional maturity are essential for effective T cell infiltration into tumors. Funding Sources NIH-NIAID AI112521 Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)