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CD8 Coreceptor to Improve TCR Gene Transfer to Treat Melanoma: Down-Regulation of Tumor-Specific Production of IL-4, IL-5, and IL-10

Laboratory of Tumor Immunology, Unit of Clinical and Tumor Immunology, Department of Medical Oncology, Erasmus Medisch Centrum (MC)-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

Therapeutic success of TCR gene transfer to treat tumors depends on the ability of redirected T cells to become activated upon tumor recognition in vivo. Help provided by tumor-specific Th1 cells is reported to relieve T cells from an anergized state and to induce tumor regression. We recently demonstrated the ability to generate melanoma-specific Th1 cells by genetic introduction of both a CD8-dependent TCR and the CD8 coreceptor into CD4⁺ T cells. In this study, we analyzed a TCR that binds Ag independently of CD8, a property generally preferred to induce tumor-specific T cell responses, and addressed the contribution of CD8 following introduction into TCR-transduced CD4⁺ T cells. To this end, primary human CD4⁺ T cells were gene transferred with a high-avidity TCR, and were shown not only to bind peptide/MHC class I, but also to effectively kill Ag-positive tumor cells in the absence of CD8. The introduction of CD8 up-regulates the tumor-specific production of TNF- and IL-2 to some extent, but significantly down-regulates production of IL-4, IL-5, and IL-10 in CD4⁺ T cells. The introduction of a mutated cysteine motif in CD8, which prevents its binding to LCK and linker for activation of T cells, did not adversely affect expression and T cell cytotoxicity, but counteracted the CD8-mediated down-regulation of IL-4 and IL-5, but not IL-10. In conclusion, CD8 down-regulates the production of major Th2-type cytokines, in part mediated by LCK and/or linker for activation of T cells, and may induce differentiation of tumor-specific Th1 cells, which makes this coreceptor an interesting candidate to improve the clinical potential of TCR gene transfer to treat cancer.

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