Tumor Necrosis Factor-α-promoted Expression of Bcl-2 and Inhibition of Mitochondrial Cytochrome c Release Mediate Resistance of Mature Dendritic Cells to Melanoma-induced Apoptosis¹

Melanoma escapes host defenses through a variety of means, including the elimination of immune effector cells within the tumor microenvironment. We have reported recently that murine and human tumors including melanoma induce premature apoptosis of dendritic cells both in vitro and in vivo. In this study, we have demonstrated that over-expression of the Bcl-2 protein family member Bcl-x_L rescued murine dendritic cells (DCs) from melanoma-induced death in vitro. Another successful protection approach was tumor necrosis factor (TNF)-α-promoted sustained expression of the antiapoptotic protein Bcl-2 within dendritic cells. This effect of TNF-α 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 micro-environment. In addition, mature DCs were more resistant to melanoma-induced apoptosis than immature dendritic cells. This finding suggests a stage-dependent sensitivity 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-induced premature apoptosis.