Interaction of CD95 ligand with its cognate receptor CD95 induces apoptotic cell death. Alterations in this pathway within tumor cells can result in escape from apoptosis and from immune surveillance. Melanoma cells recently were found to escape an immune attack via high expression of CD95 ligand, thereby inducing apoptosis of activated T lymphocytes. When screening four human melanoma cell lines for expression of CD95 and CD95 ligand, respectively, an inverse correlation was found, i.e., cells expressing high levels for CD95 ligand (CD95L(high)) were almost negative for CD95 and vice versa. Since coexpression of CD95 and CD95 ligand may lead to apoptosis by autocrine suicide or fratricide, it was tested whether overexpression of CD95 in CD95L(high) melanoma cells results in apoptotic cell death. Upon transfection with a cytomegalovirus-promoter-driven expression vector encoding the CD95 gene, CD95L(high) melanoma cells underwent apoptosis at a much higher level than CD95L(low) melanoma cells. Apoptosis appeared to be due to the activation of CD95 as cell death was inhibited by cotransfection with a dominant negative mutant for the CD95 signaling protein, Fas-associated protein with death domain. Tumor progression of CD95L(high) melanoma cells transplanted into nude mice was significantly reduced when recipient animals were injected with liposomes containing the CD95 expression vector. As demonstrated by immunohistochemistry and TUNEL staining, in vivo transfected tumor cells expressed CD95 and underwent apoptotic cell death. Hence, this study indicates that delivery of the CD95 gene inhibits tumor growth in vivo and thus might be a therapeutic strategy to treat tumor cells that express high levels of CD95 ligand. J Invest Dermatol 115:1008-1014 2000