Expression in cytotoxic T lymphocytes of a single-chain anti-carcinoembryonic antigen antibody. Redirected Fas ligand-mediated lysis of colon carcinoma

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Abstract

In the MD45 mouse cytotoxic T lymphocyte (CTL) hybridoma cell line, we have expressed a chimeric receptor, consisting of the single-chain variable domains (scFv) of anti-carcinoma embryonic antigen (CEA) mAb linked to Fcγ receptor (FcγR) chain via a CD8 hinge. Transfected MD45 subclones lysed CEA-positive human colon carcinoma cell lines in an antigen-specific and FasL-dependent manner. The degree of lysis correlated with the level of chimeric receptor expressed on transduced MD45 subclones. The requirement for an intact Y65TGL motif in the signaling γ chain suggested that interaction of the chimeric receptor with target cell CEA induced the cytotoxicity of MD45-scFv subclones. However, MD45 expressing a Y65F mutant chimera still displayed minor levels of lysis following PMA stimulation, suggesting that PMA could bypass γ chain induction of functional FasL. Pretreatment of Fas-resistant CEA-positive colon carcinoma target cells with IFN-γ increased their sensitivity of MD45-scFv subclones and FasL-mediated lysis. This study has demonstrated the successful activation of FasL function via a chimeric receptor introduced into lymphocytes and the susceptibility of human colon carcinoma to combined cytokine and CTL treatment.

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Darcy, P. K., Kershaw, M. H., Trapani, J. A., & Smyth, M. J. (1998). Expression in cytotoxic T lymphocytes of a single-chain anti-carcinoembryonic antigen antibody. Redirected Fas ligand-mediated lysis of colon carcinoma. European Journal of Immunology, 28(5), 1663–1672. https://doi.org/10.1002/(SICI)1521-4141(199805)28:05<1663::AID-IMMU1663>3.0.CO;2-L

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