Abstract

Scarcity of tumor-infiltrating T cells poses significant challenges to cancer treatment, but mechanisms that regulate T cell recruitment into the tumor microenvironment are unclear. Here we ask if the endothelial lining of tumor vasculature suppresses T cell infiltration. Using mouse pancreatic ductal adenocarcinoma models, we found that Notch signaling in endothelial cells (ECs) inhibits the pro-inflammatory functions of cancer-associated fibroblasts (CAFs) and prevents CAFs from secreting CXCL10, a chemokine that recruits anti-tumor T cells via its receptor CXCR3. Abrogation of canonical Notch signaling in ECs reprogrammed the phenotype of CAFs from myofibroblasts into pro-inflammatory fibroblasts, unleashed interferon gamma (IFN{gamma}) responses in the tumor, and stimulated CXCL10/CXCR3-mediated recruitment of T cells to inhibit tumor growth. Collectively, these data uncover an important role of endothelial Notch signaling in shaping the tumor immune microenvironment, and suggest the potential of targeting EC-CAF crosstalk as an approach to enhance anti-tumor immunity in immunologically cold tumors. In briefHow blood vasculature shapes the tumor immune microenvironment is poorly defined. This study demonstrates that tumor endothelial cells reprogram cancer-associated fibroblasts to limit anti-tumor T cell recruitment, and suggests the potential of targeting endothelium-fibroblast crosstalk to overcome T cell scarcity in "cold" tumors and enhance anti-tumor immunity.