Defective blood dendritic cells in chronic myeloid leukemia correlate with.pdf

Defective blood dendritic cells in chronic myeloid leukemia correlate with high plasmatic VEGF and are not normalized by imatinib mesylate N Boissel1, P Rousselot2, E Raffoux2, J-M Cayuela3, O Maarek3, D Charron1, L Degos2, H Dombret2, A Toubert1 and D Rea1,4 1Unite? INSERM U396 d’Immunoge?ne?tique Humaine, Institut Universitaire d’He?matologie; 2Service d’He?matologie Adulte; 3Laboratoire Central d’He?matologie; and 4Unite? de The?rapie Cellulaire et Clinique Transfusionnelle, Ho?pital Saint-Louis, Paris, France Human blood dendritic cells (DC) comprise plasmacytoid DC (PDC) and myeloid DC (MDC), which both prime antitumor T-cell responses. We prospectively monitored blood DC in 30 chronic myeloid leukemia (CML) patients before and after imatinib mesylate therapy. We found a dramatic reduction in PDC and MDC prior treatment. This reduction was associated with high plasmatic vascular endothelial growth factor (VEGF), a central regulator of angiogenesis which also participates to tumor- associated immune deficiencies. Phenotypic analysis of DC revealed in some patients a deficient expression of BDCA-4/ neuropilin-1 on PDC, a molecule involved in angiogenesis and DC-T-cell interactions. High VEGF correlated to an altered Th1/ Th2 balance in vivo and shifted PDC-induced T-cell polarization towards Th2 in vitro. Upon imatinib treatment, plasmatic VEGF rapidly decreased and a normal BDCA-4 expression was restored. PDC and MDC increased but did not reach the levels observed in healthy individuals. We conclude that VEGF may be a key player in blood DC deficiency in CML and we show that imatinib inhibits VEGF overproduction. Incomplete recovery of blood DC under imatinib despite VEGF normalization suggests a negative impact of this drug on dendritopoiesis in vivo and may result in a sustained defect in DC-mediated anti-CML responses. Leukemia (2004) 18, 1656–1661. doi:10.1038/sj.leu.2403474 Published online 2 September 2004 Keywords: VEGF; blood DC; CML; imatinib Introducti