Background: Antigen presenting cells, in particular dendritic cells (DCs),are critical elements in antitumor immunity induction. Some of the angiogenic factors released by tumorand stroma cells, including vascular endothelial growth factor (VEGF), are thought to affect DC function.Material/Methods: The expression of Vascular Endothelial Growth Factor (VEGF) isoforms VEGF-A (121, 145,165,189, 206), VEGF-C and VEGF-D were determined by immunohistochemistry, Western blotting and ELISA in 46patients with Head and Neck Squamous Cell Carcinoma (HNSCC), 30 healthy donors, and two HNSCC tumor celllines (PCI-1 and PCI-13). Results: Increased expression of VEGF-A and VEGF-C was found in tumor tissuescompared to normal epithelium (P=0.001). However, VEGF-D levels were decreased in patients with cervicalnodal metastasis as compared to patients with negative lymph node status. VEGF-A plasma levels were increasedin patients with lymph node metastasis (266 pg/ml) compared to patients with negative lymph node status(19.8 pg/ml). Multivariate analysis demonstrated that VEGF-A correlated with microvessel density (P=0.01),disease progression (P=0.038), a reduced number of local and peripheral mature dendritic cells (DC) (P=0.015)and an increased number of peripheral immature DCs (P=0.05). DCs incubated with tumor supernatant orVEGF-A differentiated into immature DCs and did not develop full allostimulatory activity. AllogenicT cells, when co-cultured with these immature DCs, expressed the T regulatory cell marker CD25, CTLA-4,and CD45Ro, and secreted TGF-beta, VEGF-A and IL-10. Conclusions: Taken together, our results identifyVEGF-A as a multifunctional factor involved in angiogenesis, tumor progression, immunosuppression andimmune tolerance.

Keywords: Head and Neck Neoplasms - blood supply, Head and Neck Neoplasms - immunology, Vascular Endothelial Growth Factors - classification, Cell Count, Coculture Techniques, Dendritic Cells - metabolism, Head and Neck Neoplasms - pathology, Immune Tolerance, Macrophages - immunology, Mucous Membrane - metabolism, Phenotype, Protein Isoforms - metabolism, T-Lymphocytes - immunology, Vascular Endothelial Growth Factors - metabolism