γδ T cells are a unique subset of T cells found in both blood (Vδ2) and tissues (Vδ1). Unlike canonical αβ T cells that recognize peptide antigens through MHC class I/II molecules, γδ T cells recognize lipids and metabolites presented by non-MHC molecules. γδ T cells are highly cytotoxic and can rapidly kill both infected and cancer cells. Their cytotoxicity and lack of MHC restriction makes γδ T cells a promising target for allogeneic cell transfer therapy. In collaboration with MRL Oncology and ID/Vax we are investigating γδ T cells as a potential “off-the-shelf” cell transfer therapy. The ESC is currently optimizing ex vivo expansion protocols for both Vδ1 and Vδ2 T cells. Vδ2 cells rapidly expand from PBMCs after exposure to Zometa/IL-2, and are efficient cancer killers in vitro. To assess activation state, targeted metabolomics analysis was performed during Vδ2 expansion, and displayed significant differences in glutamate utilization, lactic acid, myo-inositol, and several essential and non-essential amino acids. We have also isolated and expanded Vδ1 T cells from PBMCs and human tissues (colon). These cells express high levels of NKG2D, which is suggestive of cytotoxic potential and we are currently assessing their cancer cell killing capacity in vitro. In collaboration with GpGx, we are identifying the dominant T-cell receptor (TCR) repertoires present in these populations by performing sc-TCRseq, sc-REAPseq, and comprehensive immunophenotyping. The results of these assays will be used to identify the optimum expansion protocol as well as to inform on the mechanisms underlying γδ T cell cancer targeting.
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