-T cell receptor transduction gives superior mitochondrial function to æ-T cells with promising persistence

Adoptive cell therapy using allogeneic gamma delta-T cells is a promising option for off-the-shelf T cell products with a low risk of graft-versus-host disease (GVHD). Long-term persistence may boost the clinical development of gamma delta-T cell products. In this study, we found that genetically modified V gamma 9(+)V delta 2(+) T cells expressing a tumor antigen-specific alpha beta-TCR and CD8 coreceptor (GMC) showed target-specific killing and excellent persistence. To determine the mechanisms underlying these promising effects, we investigated metabolic characteristics. Cytokine secretion by gamma delta-TCR-stimulated nongene-modified gamma delta-T cells (NGMCs) and alpha beta-TCR-stimulated GMCs was equally suppressed by a glycolysis inhibitor, although the cytokine secretion of alpha beta-TCR-stimulated GMCs was more strongly inhibited by ATP synthase inhibitors than that of gamma delta-TCR-stimulated NGMCs. Metabolomic and transcriptomic analyses, flow cytometry analysis using mitochondria-labeling dyes and extracellular flux analysis consistently suggest that alpha beta-TCR-transduced gamma delta-T cells acquire superior mitochondrial function. In conclusion, alpha beta-TCR-transduced gamma delta-T cells acquire superior mitochondrial function with promising persistence.