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Experimental Therapeutics |
Department of Dermatology [L. J., J-F. A., J-H. S., C. H.] and Division of Immunology and Allergy [J-F. A., C. H.], University Hospital Geneva, 1211 Genève 14, Switzerland, and the Department of Dermatology, University Hospital Mainz, Mainz, Germany [H. J.]
Dendritic cells (DCs) phagocytose apoptotic influenza-infected monocytes
and cross-present influenza antigen to CD8+ T cells,
generating a specific CTL response. We investigated whether apoptotic
melanoma cells, presented by this mechanism, can lead to CTL responses
to tumor-associated antigens and melanoma cells. Apoptotic
HLA-A2- MEL-397 melanoma cells were internalized by
HLA-A2+ immature monocyte-derived DCs but failed to
induce maturation of DCs. When exposed to interleukin 6, interleukin
1ß, tumor necrosis factor 
, and prostaglandin
E2, DCs containing apoptotic MEL-397 cell material matured
normally [cross-presenting DCs (cp-DCs)]. Autologous CD8+
CTL lines generated with cp-DCs produced tumor necrosis factor when
stimulated with HLA-A2-binding immunodominant peptides from
MelanA/MART1 and MAGE-3 (expressed by MEL-397 cells) but not tyrosinase
(absent in MEL-397). T2 target cells loaded with the respective
peptides were lysed by these cell lines, although to a lesser extent
than by CTL lines generated in the presence of mature DCs and peptides
from melanoma-associated antigens. In contrast, lines generated with
cp-DCs lysed HLA-A2+ MEL-526 melanoma cells or allogenic
HLA-A2+ cp-DCs efficiently, whereas the CTL generated with
DCs and peptides had little lytic activity. Mature DCs containing
apoptotic tumor cells may thus represent an alternative approach for
the therapy of malignant tumors.
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