Resistance of ex vivo expanded CD3(+)CD56(+) T cells to Fas-mediated apoptosis

A variety of malignancies express Fas ligand (FasL), which can induce apopt osis in effector lymphocytes and may limit the success of cellular immunoth erapy. Our laboratory has been investigating a population of exvivo activat ed T cells, termed cytokine-induced killer (CIK) cells. These cells share f unctional and phenotypic properties with natural killer cells and a subset of cytolytic cells have the phenotype CD3(+)CD56(+). CIK cells expand in cu lture, have significant antitumor activity and are presently being tested i n phase I/II clinical trials. In this study, we investigated the sensitivit y of CIK cells to Fas-mediated apoptosis. Fas engagement leads to apoptosis in small numbers of CIK cells and does not significantly influence antitum or cytotoxicity. CIK cells will undergo apoptosis following Fas engagement when protein synthesis is inhibited, suggesting the expression of antiapopt otic genes. Evaluation of antiapoptotic gene transcripts shows an upregulat ion in the expression of cFLIP, Bcl-2, Bcl-xL, DAD1 and survivin. Resistanc e to Fas-mediated apoptosis may come about through an in vitro selection fo r Fas resistance, since CIK cells synthesize Fast and supernatant from CIK cultures contains biologically active soluble Fast, which can be inhibited with Fas:Fc. These results indicate that CIK cells are a suitable form of i mmunotherapy against Fast-positive tumors.