Down-Regulation of Cellular Vascular Endothelial Growth Factor (VEGF) Levels Induces Differentiation of Leukemic Cells into Leukemic-Dendritic Cells in Patients with Acute Myeloid Leukemia.

Vascular endothelial growth factor (VEGF), produced by most tumors, not only plays an important role in tumor angiogenesis but also can inhibit the maturation of dendritic cells (DCs) from hematopoietic progenitors. In this study, we investigated the relationship between the clinical characteristics of patients with acute myeloid leukemia (AML) and the generation of DCs from the leukemic cells, and found that cellular VEGF level in leukemic cells affected the generation of leukemic-DCs in vitro. Leukemic-DCs were successfully generated from 16 of 21 AML patients, and generated leukemic DCs exhibited high level of HLA-DR and CD54 expression, and intermediate level of CD80, CD86, CD83, and CD1a expression. Leukemic-DCs also were able to stimulate allogeneic T cell proliferation and cytotoxic activities against autologous leukemic cells. The failure of generation of leukemic-DCs from leukemic cells in some AML patients was related with its cellular VEGF levels. The leukemic cells that failed to generate leukemic-DCs had significantly higher cellular VEGF levels than that of generated leukimic-DCs (p = 0.005), and neutralizing of VEGF with anti-VEGF Ab inhibited the cellular VEGF level at the transcription level as determined by RT-PCR analysis, and at the protein level determined by West blotting and ELISA. Inhibition of cellular VEGF levels induced the generation of leukemic-DCs determined by increased levels of surface markers, namely, CD40, CD80, CD86, and HLA-DR. Moreover, inhibition of cellular VEGF levels also increased IL-12 production and allosimulatory capacity of leukemic-DCs, suggesting functional differentiation of leukemic-DCs. Interestingly, cellular VEGF levels also are inversely related to the achievement of complete remission for induction therapy (p = 0.02). Taken together, these results suggest that cellular VEGF levels during the differentiation of AML cells to leukemic-DCs are a predictive marker of the positive response of the AML patients to the remission-inducing therapy, and down-regulation of cellular VEGF levels can be one target of cancer immunotherapy by generating of sufficient number of DCs in AML patients.