Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6.
We studied concentration, phenotype, and function of peripheral blood (PB) dendritic cells (DCs) from patients with multiple myeloma (MM). The absolute number of circulating precursors of myeloid and plasmacytoid DCs was significantly lower in MM patients than in healthy subjects. After maturation, PBDCs from MM patients showed significantly lower expression of HLA-DR, CD40, and CD80 antigens and impaired induction of allogeneic T-cell proliferation compared with controls. Remarkably, they were not capable of presenting the patient-specific tumor idiotype to autologous T cells. Conversely, DCs generated in vitro from CD14(+) monocytes from the same patients, and PBDCs freshly isolated from healthy donors efficiently stimulated allogeneic and autologous T cells. To clarify the mechanism of PBDC deficiency in MM, we investigated the effects of the main plasma cell growth factor, interleukin-6 (IL-6), on the development of DCs from CD34(+) cells. IL-6 inhibited the colony growth of CD34(+) DC progenitors and switched the commitment of CD34(+) cells from DCs to CD14(+) CD1a(-) CD86(-)CD80(-) CD40(+/-)HLA-DR +/- monocytic cells exerting potent phagocytic activity but no antigen-presentation capacity. This effect was reversed by anti-IL-6 antibodies. Growing CD34(+) cells in the presence of autologous serum (without IL-6) also suppressed the development of functional DCs. This study demonstrates that PBDCs from MM patients are functionally defective, partially because of IL-6-mediated inhibition of development. This brings into question the advisability of using PBDCs as antigen carriers for immunotherapy trials in MM. The results also suggest a novel mechanism whereby myeloma cells escape immune recognition.
Ratta
Marina
M
Institute of Hematology and Medical Oncology, Lorenzo e Ariosto Seràgnoli, University of Bologna, Italy.
Fagnoni
Francesco
F
Curti
Antonio
A
Vescovini
Rosanna
R
Sansoni
Paolo
P
Oliviero
Barbara
B
Fogli
Miriam
M
Ferri
Elisa
E
Della Cuna
Gioacchino Robustelli
GR
Tura
Sante
S
Baccarani
Michele
M
Lemoli
Roberto M
RM
D017951:Antigen Presentation / Q000187:drug effects; D015703:Antigens, CD / Q000032:analysis; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007107:Immune System / Q000187:drug effects; D016130:Immunophenotyping; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D007959:Lymphocyte Culture Test, Mixed; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects
D015703:Antigens, CD; D015850:Interleukin-6; D009363:Neoplasm Proteins