Vascular endothelial growth factor impairs the functional ability of dendritic cells through Id pathways.
Vascular endothelial growth factor (VEGF) is an angiogenic cytokine that plays an important role in tumor growth and progression. Recent evidence suggests an alternate, albeit indirect, role of VEGF on host immune response to tumors. VEGF appears to diminish host immunity by altering the function of major antigen-presenting cells such as dendritic cells (DCs) [D.I. Gabrilovich, T. Ishida, S. Nadaf, J.E. Ohm, D.P. Carbone, Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function, Clin. Cancer Res. 5 (1999) 2963-2970, D. Gabrilovich, T. Ishida, T. Oyama, S. Ran, V. Kravtsov, S. Nadaf, D.P. Carbone, Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo, Blood 92 (1998) 4150-4166, T. Oyama, S. Ran, T. Ishida, S. Nadaf, L. Kerr, D.P. Carbone, D.I. Gabrilovich, Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells, J. Immunol. 160 (1998) 1224-1232.]. DCs are prime initiators of host immunity as they are known to activate both primary as well as secondary immune responses [J. Banchereau, F. Briere, C. Caux, J. Davoust, S. Lebecque, Y.J. Liu, B. Pulendran, K. Palucka, Immunobiology of dendritic cells, Ann. Rev. Immunol. 18 (2000) 767-811.]. However, the exact nature of how VEGF suppresses DC function is not fully clear. In this report, we show that DCs cultured in the presence of VEGF are less potent in stimulating antigen-specific T-cells. Furthermore, by using DCs derived from Id1(-/-) mice that are defective in Flt-1 signaling, we demonstrated that the inhibitory function of VEGF on DC function is most likely mediated by Flt-1. Thus, the role of VEGF in downregulating host immunity may highlight a unique role of VEGF in the pathogenesis of cancer.
Laxmanan
Sreenivas
S
Department of Pathology, Beth Israel Deaconess Medical Center School, Harvard Medical School, Boston, MA, USA.|Division of Nephrology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
Robertson
Stuart W
SW
Division of Nephrology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
Wang
Enfeng
E
Department of Pathology, Beth Israel Deaconess Medical Center School, Harvard Medical School, Boston, MA, USA.|Department of Biochemistry and Molecular Biology, Mayo Clinic Cancer Center, Mayo Clinic Foundation, Rochester, MN, USA.
Lau
Julie S
JS
Department of Biochemistry and Molecular Biology, Mayo Clinic Cancer Center, Mayo Clinic Foundation, Rochester, MN, USA.
Briscoe
David M
DM
Division of Nephrology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
Mukhopadhyay
Debabrata
D
Department of Pathology, Beth Israel Deaconess Medical Center School, Harvard Medical School, Boston, MA, USA.|Department of Biochemistry and Molecular Biology, Mayo Clinic Cancer Center, Mayo Clinic Foundation, Rochester, MN, USA.
D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism*; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1; D051379:Mice; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C497453:ID1 protein, human; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D012097:Repressor Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A