Abstract
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.
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Acknowledgements
We thank Dr Lionel Adès, Dr Jean-Marc Zini and staff members from the clinical investigation center from Saint Louis hospital for help with collecting patients samples.
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This work was supported by a grant from La Fondation de France (2002-2386), la Délégation Régionale à la Recherche Clinique de l'Assistance Publique des Hôpitaux de Paris and Allostem (FP6 #503319).
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Boissel, N., Rousselot, P., Raffoux, E. et al. Defective blood dendritic cells in chronic myeloid leukemia correlate with high plasmatic VEGF and are not normalized by imatinib mesylate. Leukemia 18, 1656–1661 (2004). https://doi.org/10.1038/sj.leu.2403474
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DOI: https://doi.org/10.1038/sj.leu.2403474
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