Immune escape of tumors in vivo by expression of cellular FLICE-inhibitoryprotein

The antiapoptotic protein cellular FLICE (Fas-associated death domain-like IL-1 beta-converting enzyme) inhibitory protein (cFLIP) protects cells from CD95(APO-1 /Fas)-induced apoptosis in vitro and was found to be overexpres sed in human melanomas. However, cytotoxic T cell-induced apoptosis, which is critically involved in tumor control in vivo, is not inhibited by cFLIP in vitro, as only CD95- and not perforin-dependent lysis is affected. This calls into question whether cFLIP is sufficient to allow escape from T cell -dependent immunity. Using two murine tumors, we directly demonstrate that cFLIP does result in escape from T cell immunity in vivo. Moreover, tumor c ells are selected in vivo for elevated cFLIP expression. Therefore, our dat a indicate that CD95-dependent apoptosis constitutes a more prominent mecha nism for tumor clearance than has so far been anticipated and that blockade of this pathway can result ill tumor escape even when the perforin pathway is operational.