CD40·FasL and CTLA-4·FasL fusion proteins induce apoptosis in malignant cell lines by dual signaling.

Evolution of apoptosis resistance in both lymphoma and leukemia cells is well documented and induction of apoptosis in malignant cells is a major goal of cancer therapy Up regulation of anti apoptotic signals is one of the mechanisms whereby resistance to apoptosis emerges We have previously described the fusion proteins CD40 FasL and CTLA 4 FasL, which are formed from two functional membrane proteins and induce apoptosis of activated T cells The present study explores the potential use of CD40 FasL and CTLA 4 FasL for the killing of malignant cells of lymphatic origin Using malignant B and T cell lines that differ in surface expression of costimulatory molecules we found that CTLA 4 FasL induces effective apoptosis of cells expressing CD95 and activates caspases 3 8 and 9 Only B7 expressing B cells responded to CTLA 4 FasL with rapid abrogation of cFLIP expression CD40 FasL effectively killed only the T cells that express high levels of CD40L in addition to CD95 In these cells CD40 FasL significantly diminished cFLIP expression Importantly, each of the fusion proteins is more potent than its respective components parts alone or, m combination Thus the proteins with their two functional ends deliver a pro apoptotic signal and in parallel inhibit an anti apoptotic signal thus optimizing the wanted death inducing effect Therefore these proteins emerge as promising agents to be used for targeted and specific tumor cell killing (Am J Pathol 2010 177 3159-316 DOI 10 2353/ajpath 2010 100301)