Resistance of ex vivo expanded CD3+CD56+ T cells to Fas-mediated apoptosis.
A variety of malignancies express Fas ligand (FasL), which can induce apoptosis in effector lymphocytes and may limit the success of cellular immunotherapy. Our laboratory has been investigating a population of ex vivo activated T cells, termed cytokine-induced killer (CIK) cells. These cells share functional and phenotypic properties with natural killer cells and a subset of cytolytic cells have the phenotype CD3+CD56+. CIK cells expand in culture, have significant antitumor activity and are presently being tested in phase I/II clinical trials. In this study, we investigated the sensitivity of CIK cells to Fas-mediated apoptosis. Fas engagement leads to apoptosis in small numbers of CIK cells and does not significantly influence antitumor cytotoxicity. CIK cells will undergo apoptosis following Fas engagement when protein synthesis is inhibited, suggesting the expression of antiapoptotic genes. Evaluation of antiapoptotic gene transcripts shows an upregulation in the expression of cFLIP, Bcl-2, Bcl-xL, DAD1 and survivin. Resistance to Fas-mediated apoptosis may come about through an in vitro selection for Fas resistance, since CIK cells synthesize FasL and supernatant from CIK cultures contains biologically active soluble FasL, which can be inhibited with Fas:Fc. These results indicate that CIK cells are a suitable form of immunotherapy against FasL-positive tumors.
Verneris
M R
MR
Division of Bone Marrow Transplantation, Stanford University School of Medicine, CA 94305, USA.
Kornacker
M
M
Mailänder
V
V
Negrin
R S
RS
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D029681:Arabidopsis Proteins; D017252:CD3 Complex / Q000032:analysis*; D019002:CD56 Antigen / Q000032:analysis*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D044943:Fatty Acid Desaturases / Q000032:analysis; D006801:Humans; D007694:Killer Cells, Natural / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000032:analysis; D008565:Membrane Proteins / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D019014:fas Receptor / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D029681:Arabidopsis Proteins; D017252:CD3 Complex; D019002:CD56 Antigen; C083331:DAD1 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D019014:fas Receptor; D003513:Cycloheximide; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis