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Immunology 5: Dendritic Cells and Immune Regulation

Abstract #3140

Neuroblastoma inhibit dendritic cell maturation by expressing phosphatidylserine on the cell surface

Medical College of Wisconsin, Milwaukee, WI

The mechanisms by which neuroblastoma (NB), a childhood malignancy with poor prognosis, inhibits DC maturation are not well understood. We made the novel observation that NB cells express phosphatidylserine (PS) on the cell surface. PS is an anionic phosphalipid restricted to the cytoplasmic side of the plasma membrane bilayer in most live cells and externalized early in the process of apoptosis. The effect of exposure to NB-PS on DC maturation and function was examined. DCs, generated from donor PBMCs in the presence of GM-CSF and IL-4, were exposed to NB cells and treated with TNF± or LPS to induce maturation. DC maturation was assessed using flow cytometry and cytokine production was assayed using ELISA. DCs were used to stimulate allogeneic T cells and proliferation was detected using [3H]-Thymidine incorporation and CFSE profiling. NB cells inhibited expression of MHCII, CD80, CD86 and CD83, production of IL-12, TNF-alpha and IL-6 and ability to activate allogeneic T cells by DCs. Separating DCs and NB cells using transwells prevented the inhibitory effect on maturation. Similarly blocking PS on the surface of NB cells using Annexin-V (AnV), a protein that binds PS specifically, attenuated the inhibitory effect on DC maturation. Blocking IL-10, TGF-beta, VEGF or the ganglioside GD2 did not prevent the inhibitory effect of NB cells on DC maturation. In summary, PS, on the surface of NB cells, inhibits DC maturation and immunostimulatory function. Expressing PS on the cell surface may be a novel mechanism for modulating the immune response and evading destruction by NB.