GSE186046
Endothelial Rap1B mediates VEGF immunosuppression
Overcoming vascular immunosuppression: lack of endothelial cell (EC) responsiveness to inflammatory stimuli in the proangiogenic environment of tumors, is essential for successful cancer immunotherapy. The mechanisms through which Vascular Endothelial Growth Factor (VEGF) modulates tumor EC response to exclude T cells are not well understood. The goal was to determine the role of EC Rap1B, a small GTPase that positively regulates VEGF-angiogenesis during development, in tumor growth in vivo. Using mouse models of Rap1B deficiency, Rap1B+/- and endothelial-specific Rap1B KO (Rap1Bi?EC) we demonstrate Rap1B restricts tumor growth and angiogenesis. More importantly, EC-specific Rap1B deletion leads to an altered tumor microenvironment with increased recruitment of leukocytes and increased activity of tumor CD8+ T cells. We find that tumor growth, albeit not angiogenesis, is restored in Rap1Bi?EC mice by depleting CD8+ T cells.  Mechanistically, global transcriptome analysis indicated upregulation of the TNF-a signaling and cytokine-induced NF?B transcriptional activity in Rap1B-deficient ECs. In particular, endothelial Rap1B deletion led to upregulation of Cell Adhesion Molecules  (CAMs) expression in response to proinflammatory cytokines, and increased interaction with leukocytes in vitro. Importantly, deletion of Rap1 abrogated VEGF-mediated inhibition of CAM expression, demonstrating that Rap1B is essential for mediating VEGF-suppressive signaling. Thus, our studies identify a novel endothelial-endogenous mechanism underlying VEGF-dependent desensitization of EC to pro-inflammatory stimuli. Significantly, they identify EC Rap1 as a potential novel vascular target in cancer immunotherapy. Overall design: Bulk RNAseq of siRap1B- and siControl-transfected HUVECs