Tumoricidal activity of monocyte-derived dendritic cells: Evidence for a caspase-8-dependent, Fas-associated death domain-independent mechanism

Monocyte-derived dendritic cells (DC) were found to be cytotoxic for severa l tumor cell lines including Jurkat cells, which were killed through a calc ium-independent pathway. K562 cells were resistant, excluding a NK cell-lik e activity. DC-mediated apoptosis did not involve classical death receptors because it was not reversed by blocking TNF/TNFR, CD95/CD95 ligand, or TNF -related apoptosis-inducing ligand/TNF-related apoptosis-inducing ligand re ceptor interactions. Fas-associated death domain-deficient, but not caspase -8 deficient, Jurkat cells were killed by DC. Indeed, caspase-8 cleavage wa s demonstrated in Jurkat cells cocultured with DC, and the use of specific caspase inhibitors confirmed that apoptosis triggered by DC was caspase-8 d ependent. Furthermore, the involvement of Bcl-2 family members in the contr ol of DC-mediated apoptosis was demonstrated by Bid cleavage in Jurkat cell s cocultured with DC and resistance of Jurkat cells overexpressing Bcl-2 to DC-mediated cytotoxicity. Overall, these data indicate that monocyte-deriv ed DC exert a caspase-8-dependent, Fas associated death domain-independent tumoricidal activity, a finding that could be relevant to their therapeutic use in cancer.