TNF-RELATED APOPTOSIS-INDUCING LIGAND (TRAIL) INDUCES APOPTOSIS IN FAS LIGAND-RESISTANT MELANOMA-CELLS AND MEDIATES CD4 T-CELL KILLING OF TARGET-CELLS

We have previously shown that melanoma cells were resistant to apoptos is induced by TNF family members Fas ligand (FasL), TNF-alpha, and CD4 0L. Fast also was not involved in CD4 T cell-mediated killing of melan oma cells, In the present study, we have tested melanoma cells for the ir susceptibility to apoptosis induced by human TNF-related apoptosis- inducing ligand (TRAIL) and the ability of a mAb against TRAIL to inhi bit apoptosis and CD4 CTL-mediated killing of melanoma and Jurkat targ et cells. The results show that TRAIL-induced apoptosis in cells from 7 of 10 melanoma cell lines tested as well as in Jurkat T cells, Susce ptibility to apoptosis was increased in some of the tell lines by trea tment with cyclohexamide or actinomycin D. The melanoma cells were res istant to apoptosis induced by Fast, TNF-alpha, and CD40L. mAb M180 ag ainst TRAIL inhibited apoptosis induced by TRAIL. It was also found to inhibit CD4 CTL-mediated killing of Jurkat T cells as well as autolog ous and allogeneic melanoma cells, The degree of inhibition produced b y the mAb varied between different clones of CTL and according to the susceptibility of the target cells to TRAIL-induced apoptosis, These r esults suggest that TRAIL is an important mediator of cell death induc ed by CTL and may have an important therapeutic role against human mel anoma.