The T cell death knell: Immune-mediated tumor death in renal cell carcinoma

The antitumor effect of T cells is executed either through CD95 or Perforin (PFN)/Granzyme B (GrB) pathways. Induction of apoptosis by either mode req uires activation of caspase family members. However, recent studies have su ggested that cell death can proceed in the absence of caspase induction and apoptotic events. We investigated the contribution of CD95 and PFN/GrB-med iated cytotoxicity to apoptotic and necrotic mechanisms of cell death in hu man renal cell carcinoma. Although freshly isolated and cultured tumors exp ressed CD95 on their surface, they were resistant to CD95-mediated apoptosi s. CD95 resistance coincided With decreased levels of FADD protein and dimi nished caspase-3-like activity. In contrast, we demonstrated that tumor cel l death mediated by PFN/GrB can be achieved in the absence of functional ca spase activity and is accompanied by a dramatic accumulation of nonapoptoti c necrotic cells.