Tumor-Infiltrating CD4+ T Lymphocytes Express APO2 Ligand (APO2L)/TRAIL upon Specific Stimulation with Autologous Lung Carcinoma Cells: Role of IFN-α on APO2L/TRAIL Expression and -Mediated Cytotoxicity

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Abstract
In the present report, we have investigated TRAIL/APO2 ligand (APO2L) expression, regulation, and function in human lung carcinoma tumor-infiltrating lymphocytes. Using a panel of non-small cell lung carcinoma cell lines, we first showed that most of them expressed TRAIL-R1/DR4, TRAIL-R2/DR5, but not TRAIL-R3/DcR1 and TRAIL-R4/DcR2, and were susceptible to APO2L/TRAIL-induced cell death. Two APO2L/TRAIL-sensitive tumor cell lines (MHC class I+/II+ or I+/II−) were selected and specific CD4+ HLA-DR- or CD8+ HLA-A2-restricted CTL clones were respectively isolated from autologous tumor-infiltrating lymphocytes. Interestingly, although the established T cell clones did not constitutively express detectable levels of APO2L/TRAIL, engagement of their TCR via activation with specific tumor cells selectively induced profound APO2L/TRAIL expression on the CD4+, but not on the CD8+, CTL clones. Furthermore, as opposed to the CD8+ CTL clone which mainly used granule exocytosis pathway, the CD4+ CTL clone lysed the specific target via both perforin/granzymes and APO2L/TRAIL-mediated mechanisms. The latter cytotoxicity correlated with APO2L/TRAIL expression and was significantly enhanced in the presence of IFN-α. More interestingly, in vivo studies performed in SCID/nonobese diabetic mice transplanted with autologous tumor and transferred with the specific CD4+ CTL clone in combination with IFN-α resulted in an important APO2L/TRAIL-mediated tumor growth inhibition, which was prohibited by soluble TRAIL-R2. Our findings suggest that APO2L/TRAIL, specifically induced by autologous tumor and up-regulated by IFN-α, may be a key mediator of tumor-specific CD4+ CTL-mediated cell death and point to a potent role of this T cell subset in tumor growth control.