Rapid αβ TCR-mediated responses in γδ T cells transduced with cancer-specific TCR genes

Adoptive T-cell transfer of in vitro cultured T cells derived from cancer patients with naturally developed immune responses has met with some success as an immunotherapeutic approach, although only a limited number of patients showed spontaneous immune responses. To find alternative ways, such as cancer-specific T-cell receptor (TCR) gene transfer, in preparation for sufficient numbers of antigen-specific T cells is an important issue in the field of adoptive T-cell therapy. Given the inherent disadvantage of αβ TCR transfer to other αβ T cells, namely the possible formation of mixed TCR heterodimers with endogenous α or β TCR, we employed γδ T cells as a target for retroviral transfer of cancer-specific TCR and examined whether γδ T cells were useful as an alternative population for TCR transfer. Although retroviral transduction to γδ T cells with TCR αβ genes alone, isolated from a MAGE-A4 143-151 -specific αβ CD8 + cytotoxic T lymphocyte (CTL) clone, did not provide sufficient affinity to recognize major histocompatibility (MHC)-peptide complexes due to the lack of CD8 co-receptor, γδ T cells co-transduced with TCR αβ and CD8 αβ genes acquired cytotoxicity against tumor cells and produced cytokines in both αβ- and γδ-TCR-dependent manners. Furthermore, αβ TCR and CD8-transduced γδ T cells, stimulated either through αβ TCR or γδ TCR, rapidly responded to target cells compared with conventional αβ T cells, reminiscent of γδ T cells. We propose αβ TCR-transduced γδ T cells as an alternative strategy for adoptive T-cell transfer.