Induction of apoptosis in experimental human B cell lymphomas by conditional TRAIL-expressing T cells.
In the present study, we demonstrate the utility of a non-tumour-forming T-cell line for the inducible gene transfer of tumour necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL), which has been shown to selectively induce apoptosis in malignant but not in normal cells. To generate T cells inducible for TRAIL expression, we stably transfected Jurkat cells with TRAIL in the context of the Tet-On system. The switched on cells strongly expressed TRAIL mRNA, whose protein product was expressed on the cell surface. Paracrine induction of apoptosis in human target tumour cells was solely found for membrane-bound TRAIL. The Jurkat-TRAIL cells itself survived due to clonal selection of TRAIL-resistant cells. Jurkat-TRAIL cells had an additive effect with cytotoxic drugs in vitro, since cell death was enhanced. To elucidate the antitumoral activity of these Jurkat-TRAIL cells in vivo, we injected them intratumorally in xenografts of human Burkitt lymphomas. Switching on expression of TRAIL by adding tetracycline to the drinking water of the mice strongly reduced tumour growth by apoptosis in a caspase-dependent manner. Thus, non-tumour-forming T-cell lines offer a novel method for gene transfer and inducible expression of TRAIL in tumour therapy.
Ucur
E
E
Clinical Cooperation Unit, Molecular Oncology/Pediatrics, German Cancer Research Center, Heidelberg, Germany.
Mattern
J
J
Wenger
T
T
Okouoyo
S
S
Schroth
A
A
Debatin
K-M
KM
Herr
I
I
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002051:Burkitt Lymphoma / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D018014:Gene Transfer Techniques; D006801:Humans; D019169:Jurkat Cells; D016393:Lymphoma, B-Cell / Q000473:pathology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013601:T-Lymphocytes / Q000637:transplantation; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha