Tumor necrosis factor-alpha-promoted expression of Bcl-2 and inhibition ofmitochondrial cytochrome c release mediate resistance of mature dendritic cells to melanoma-induced apoptosis

Melanoma escapes host defenses through a variety of means, including the el imination of immune effector cells within the tumor microenvironment, We ha ve reported recently that murine and human tumors including melanoma induce premature apoptosis of dendritic cells both ill vitro and in vivo. In this study, we have demonstrated that overexpression of the Bcl-2 protein famil y member Bcl-x(L) rescued murine dendritic cells (DCs) from melanoma-induce d death in vitro. Another successful protection approach was tumor necrosis factor (TNF)-alpha -promoted sustained expression of:the antiapoptotic pro tein Bcl-2 within dendritic cells, This effect of TNF-alpha was mediated by inhibition of mitochondrial cytochrome c release. Thus, both Bcl-x(L) and Bcl-2 enhance survival of dendritic cells within the tumor microenvironment . In addition, mature DCs were more resistant to melanoma-induced apoptosis than immature dendritic cells, This finding suggests a stage-dependent sen sitivity of DCs to: tumor-induced cell death, We conclude that: (a) mature DCs might be more suitable for the use of cancer vaccination; and (b) Bcl-2 protein family members such as Bcl-x(L) and Bcl-2 rescue DCs from tumor-in duced premature apoptosis.