Tumor secretion of VEGF induces endothelial cells to suppress T cell functions through the production of PGE2.
Endothelial cells are potent regulators of immune cell functions and have therefore been examined to determine their role in tumor-induced immune suppression. Previous studies by our laboratory showed that exposure to Lewis lung carcinoma (LLC)-secreted products induced endothelial cells to suppress T-cell functions in vitro. The current studies examined in vitro and in vivo the mechanism by which tumors induce the formation of suppressor endothelial cells and the means by which suppressor endothelial cells disrupt T-cell functions. In vitro studies demonstrated that inhibition of tumor-derived VEGF with neutralizing antibodies or treatment of endothelial cells with the VEGF receptor tyrosine kinase inhibitor, SU5416, prevented endothelial cells from being induced to suppress T-cell functions. Treatment of tumor-bearing mice with SU5416 blocked the development of endothelial cells that are suppressive to CD4 and CD8 T-cell functions. We next examined the role of suppressor endothelial cell-derived PGE2 in the inhibition of T-cell functions. Abrogation of endothelial cell PGE2 production in vitro with indomethacin prevented tumor-conditioned media from stimulating endothelial cell production of immune inhibitory activity toward T-cell functions. Similar treatment of endothelial cells from lungs of tumor-bearing mice blocked their capacity to produce T-cell-inhibitory mediators. These studies demonstrate that tumor-derived VEGF induces endothelial cells to upregulate production of PGE2 which, in turn, leads to suppression of T-cell functions.
Department of Otolaryngology, Medical University of South Carolina, Charleston, SC, USA.
Jennifer K
JK
Mulligan
Steven A
SA
Rosenzweig
M Rita I
MR
Young
D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D015232:Dinoprostone / Q000276:immunology* / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019139:Tumor Escape; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology / Q000378:metabolism*
D057134:Antibodies, Neutralizing; D015703:Antigens, CD; D007211:Indoles; D007376:Interleukin-2; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib; D007371:Interferon-gamma; D015232:Dinoprostone; D007213:Indomethacin