Defective blood dendritic cells in chronic myeloid leukemia correlate with high plasmatic VEGF and are not normalized by imatinib mesylate.
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.
Boissel
N
N
Unité INSERM U396 d'Immunogénétique Humaine, Institut Universitaire d'Hématologie, Paris, France.
Rousselot
P
P
Raffoux
E
E
Cayuela
J-M
JM
Maarek
O
O
Charron
D
D
Degos
L
L
Dombret
H
H
Toubert
A
A
Rea
D
D
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*
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