Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: Role of interleukin-6 and macrophage colony-stimulatingfactor

The escape of malignant cells from the immune response against the tumor ma y result from a defective differentiation or function of professional antig en-presenting cells (APC), ie, dendritic cells (DC). To test this hypothesi s, the effect of human renal cell carcinoma cell lines (RCC) on the develop ment of DC from CD34(+) progenitors was investigated in vitro. RCC cell lin es were found to release soluble factors that inhibit the differentiation o f CD34(+) cells into DC and trigger their commitment towards monocytic cell s (CD14(+)CD64(+)CD1a(-)CD86(-)CD80(-)HLA-DRlow) with a potent phagocytic c apacity but lacking APC function. RCC CM were found to act on the two disti nct 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: antibodie s against IL-6 and M-CSF abrogated the inhibitory effects of RCC CM; and re combinant IL-6 and/or M-CSF inhibited the differentiation of DC similarly t o RCC CM, The inhibition of DC differentiation by RCC CM was preceeded by a n induction of M-CSF receptor (M-CSFR; CD115) and a loss of granulocyte-mac rophage colony-stimulating factor receptor alpha (GM-CSFR alpha; CD116) exp ression 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 togethe r, the results suggest that the inhibition of DC development could represen t a frequent mechanism by which tumor cells will escape immune recognition. (C) 1998 by The American Society of Hematology.