title: Defective blood dendritic cells in chronic myeloid leukemia correlate with high plasmatic VEGF and are not normalized by imatinib mesylate.
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.
authors.affiliation: Unité INSERM U396 d'Immunogénétique Humaine, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Boissel
authors.forename: P
authors.initials: P
authors.lastname: Rousselot
authors.forename: E
authors.initials: E
authors.lastname: Raffoux
authors.forename: J-M
authors.initials: JM
authors.lastname: Cayuela
authors.forename: O
authors.initials: O
authors.lastname: Maarek
authors.forename: D
authors.initials: D
authors.lastname: Charron
authors.forename: L
authors.initials: L
authors.lastname: Degos
authors.forename: H
authors.initials: H
authors.lastname: Dombret
authors.forename: A
authors.initials: A
authors.lastname: Toubert
authors.forename: D
authors.initials: D
authors.lastname: Rea
mesh_terms: D000328:Adult; D000368:Aged; D000954:Antigens, Surface / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D001773:Blood Cells; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology*; D039942:Neuropilin-1 / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D011446:Prospective Studies; D011743:Pyrimidines / Q000627:therapeutic use*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*
chemical_list: D000954:Antigens, Surface; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D042461:Vascular Endothelial Growth Factor A; C478196:blood dendritic cell antigen 4, human; D039942:Neuropilin-1; D000068877:Imatinib Mesylate