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The T Cell Death Knell

Immune-mediated Tumor Death in Renal Cell Carcinoma¹

Departments of Immunology [R. G. U., V. K., C. T., L. M., R. B., J. H. F.], Urology [R. G. U., A. C. N., R. B., J. H. F.], and Experimental Therapeutics [V. K., C. T., L. M., R. B., J. H. F.], The Cleveland Clinic Foundation, Cleveland, Ohio 44195; Department of Medicine, Evanston Hospital, Northwestern University, Evanston, Illinois 60208 [C. J. F.]; Department of Urology, Division of Urologic Oncology, The New York Hospital Cornell University Medical Center, New York, New York 60208 [N. H. B.]

The antitumor effect of T cells is executed either through CD95 or Perforin (PFN)/Granzyme B (GrB) pathways. Induction of apoptosis by either mode requires activation of caspase family members. However, recent studies have suggested that cell death can proceed in the absence of caspase induction and apoptotic events. We investigated the contribution of CD95 and PFN/GrB-mediated cytotoxicity to apoptotic and necrotic mechanisms of cell death in human renal cell carcinoma. Although freshly isolated and cultured tumors expressed CD95 on their surface, they were resistant to CD95-mediated apoptosis. CD95 resistance coincided with decreased levels of FADD protein and diminished caspase-3-like activity. In contrast, we demonstrated that tumor cell death mediated by PFN/GrB can be achieved in the absence of functional caspase activity and is accompanied by a dramatic accumulation of nonapoptotic necrotic cells.

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