title: Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor.
abstract: The escape of malignant cells from the immune response against the tumor may result from a defective differentiation or function of professional antigen-presenting cells (APC), ie, dendritic cells (DC). To test this hypothesis, the effect of human renal cell carcinoma cell lines (RCC) on the development of DC from CD34(+) progenitors was investigated in vitro. RCC cell lines were found to release soluble factors that inhibit the differentiation of CD34(+) cells into DC and trigger their commitment towards monocytic cells (CD14(+)CD64(+)CD1a-CD86(-)CD80(-)HLA-D Rlow) with a potent phagocytic capacity but lacking APC function. RCC CM were found to act on the two distinct subpopulations emerging in the culture at day 6 ([CD14(+)CD1a-] and [CD14(-)CD1a+]) by inhibiting the differentiation into DC of [CD14(+)CD1a-] precursors and blocking the acquisition of APC function of the [CD14(-)CD1a+] derived DC. Interleukin-6 (IL-6) and macrophage colony-stimulating factor (M-CSF) were found to be responsible for this phenomenon: antibodies against IL-6 and M-CSF abrogated the inhibitory effects of RCC CM; and recombinant IL-6 and/or M-CSF inhibited the differentiation of DC similarly to RCC CM. The inhibition of DC differentiation by RCC CM was preceeded by an induction of M-CSF receptor (M-CSFR; CD115) and a loss of granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR; CD116) expression at the surface of CD34(+) cells, two phenomenon reversed by anti-IL-6/IL-6R and anti-M-CSF antibodies, respectively. Finally, a panel of tumor cell lines producing IL-6 and M-CSF induced similar effects. Taken together, the results suggest that the inhibition of DC development could represent a frequent mechanism by which tumor cells will escape immune recognition.
authors.affiliation: Unité Cytokine et Cancer, Unité INSERM 453, Centre Léon Bérard, Lyon, France; and Schering Plough, Dardilly, France.
authors.forename: C
authors.initials: C
authors.lastname: Menetrier-Caux
authors.forename: G
authors.initials: G
authors.lastname: Montmain
authors.forename: M C
authors.initials: MC
authors.lastname: Dieu
authors.forename: C
authors.initials: C
authors.lastname: Bain
authors.forename: M C
authors.initials: MC
authors.lastname: Favrot
authors.forename: C
authors.initials: C
authors.lastname: Caux
authors.forename: J Y
authors.initials: JY
authors.lastname: Blay
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D018952:Antigens, CD34 / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000276:immunology / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016130:Immunophenotyping; D015850:Interleukin-6 / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*; D008222:Lymphokines / Q000276:immunology / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D000906:Antibodies; D018952:Antigens, CD34; D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; D015850:Interleukin-6; D008222:Lymphokines; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor