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Immunology |
University of Pittsburgh Cancer Institute [T. K. H., N. M., G. D., H. K., T. L. W.] and Department of Pathology [T. L. W.], University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
It has been suggested that dendritic cells (DCs) are capable of
ingesting apoptotic tumor cells (ATCs) and presenting tumor-associated
antigens to immune cells. We evaluated the potential of human DCs,
which have ingested ATCs, to serve as a source of antigenic epitopes
for presentation to T cells specific for PCI-13, a squamous cell
carcinoma of the head and neck cell line. Immature DCs
(DCimm) generated in the presence of interleukin 4 and
granulocyte machrophage colony-stimulating factor from peripheral blood
monocytes of HLA-A2+ healthy donors were incubated in the
presence of ATCs. Uptake of ATCs by DCs was monitored by flow cytometry
and confocal microscopy after 2–18 h of coincubation. When DCs were
matured (DCmat) in the presence of proinflammatory
cytokines, their capacity to uptake ATCs was reduced. Responses of
PCI-13-specific CD8+ T cells to unmodified PCI-13 cells and
to DCimm or DCmat +/- ATCs or +/- tumor
lysates were tested in 
-IFN enzyme-linked immunospot and
cytotoxicity assays. Unmodified tumor cells were found to be the best
stimulators of antitumor activity of the established T-cell line, and
ATCs alone were minimally stimulatory. However, DCs that ingested ATCs
were able to present tumor antigens to CTLs, and DCimm and
DCmat were almost equally stimulatory. When DCs plus
various tumor-derived preparations were used as antigen-presenting
cells with autologous HLA-A2+ T cells obtained from normal
donors, DCs that had ingested ATCs were more effective in generating
CD8+ CTLs than tumor cells alone or DCs pulsed with tumor
lysates. The results indicate that human DCs fed with ATCs and then
matured effectively generated T cell-mediated antitumor responses
in vitro.
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