Interferon-γ produced by tumor-infiltrating NK cells and CD4+ T cells downregulates TNFSF15 expression in vascular endothelial cells

Endothelial cells in an established vasculature secrete tumor necrosis factor superfamily-15 (TNFSF15; VEGI; TL1A) that functions as a negative modulator of neovascularization to maintain blood vessel stability. TNFSF15 gene expression diminishes at angiogenesis and inflammation sites such as in cancers and wounds. We reported previously that vascular endothelial growth factor and monocyte chemotactic protein-1 contribute to TNFSF15 downmodulation in ovarian cancer. Here we show that interferon-gamma (IFN gamma) suppresses TNFSF15 expression in human umbilical vein endothelial cells. This activity is mediated by IFN gamma receptor and the transcription factor STAT1. Immunohistochemical analysis of ovarian cancer clinical specimens indicates that TNFSF15 expression diminishes while tumor vascularity increases in specimens with high-grades of IFN gamma expression. Since tumor-infiltrating NK and CD4(+) T cells are the main sources of IFN gamma in tumor lesions, we isolated these cells from peripheral blood of healthy individuals, treated the cells with ovarian cancer OVCAR3 cell-conditioned media, and found a onefold and tenfold increase of IFN gamma production in NK and CD4(+) T cells, respectively, compared with that in vehicle-treated cells. These findings support the view that tumor-infiltrating NK and CD4(+) T cells under the influence of cancer cells significantly increase the production of IFN gamma, which in turn inhibits TNFSF15 expression in vascular endothelial cells, shifting the balance of pro- and anti-angiogenic factors toward escalated angiogenesis potential in the tumor.