Tumor-induced apoptosis of T cells: Amplification by a mitochondrial cascade

We have recently reported that apoptosis of T cells induced by squamous cel l carcinoma of the head and neck (SCCHN) is partly Fas dependent. This tumo r-induced T-cell death is mediated by the activities of caspase-8 and caspa se-9 and is partially inhibited by antibodies to either Fas or Fas ligand. We report here that in contrast to apoptosis induced by agonistic anti-Fas antibody (Ab), the tumor-induced apoptotic cascade in Jurkat cells is signi ficantly amplified by a mitochondrial loop. The involvement of mitochondria In tumor-induced apoptosis of T cells was demonstrated by changes in mitoc hondrial permeability transition as assessed by 3,3'-dihexiloxadicarbocyani ne staining, by cleavage of cytosolic BID and its translocation to the mito chondria, by release of cytochrome c to the cytosol, and by the presence of active subunits of caspase-9 in jurkat T cells cocultured with tumor cells . To further elucidate the significance of mitochondria in tumor-induced T- cell death, we investigated the effects of various inhibitors of the mitoch ondrial pathway. Specific antioxidants, as well as two inhibitors of mitoch ondria permeability transition, bongkrekic acid and cyclosporin A, signific antly blocked the DNA degradation induced in Jurkat T cells by SCCHN cells. However, these inhibitors had no effect on cells triggered by anti-Pas Ab, Furthermore, a cell-permeable inhibitor of caspase-9, Ac-LEHD.CHO, which d id not inhibit T-cell apoptosis induced by anti-Fas Ab, markedly inhibited apoptosis induced by etoposide or by coculture of Jurkat with SCCHN cells. These findings demonstrate that apoptotic cascades induced in Jurkat T lymp hocytes by anti-Fas Ab or tumor cells are differentially susceptible to a p anel of inhibitors of mitochondrial apoptotic events. It appears that besid es the Fas-mediated pathway, additional mitochondria-dependent cascades are involved in apoptosis of tumor-associated lymphocytes. Inhibition of mitoc hondria-dependent cascades of caspase activation should be considered to en hance the success of immunotherapy or vaccination protocols in cancer.