Vascular normalization confers an endothelial immune suppressive gene expression profile

The efficacy of immunotherapy is commonly increased by simultaneous anti-angiogenesis treatment. An experimental breast cancer model exhibits vascular normalization with reduced vascular leakage when grown in mice with endothelial Shb deficiency. This mutant ablates the effects of vascular endothelial growth factor A on angiogenesis and leakage. Unexpectedly, the endothelial gene expression changes that were observed under these conditions suggested an immunosuppressive state. Comparison of healthy human breast endothelium with breast cancer endothelium revealed similar immune suppressive gene expression differences, and lung cancer and colorectal cancer showed analogous patterns of changes. These findings suggest that normalized or physiologically normal endothelium may have immunosuppressive features, with implications for the optimization of cancer immunotherapy regimens.