| Summary: | Background: γδ T-cells can kill multiple cancer types and virally infected cells independent of human leukocyte antigen (HLA). Targeting is believed to occur via recognition of generic, unidentified, stress signals at the target cell surface via the γδ T-cell receptor (TCR). Consequently, γδ TCR and its ligands offer potential for pan-population, off-the-shelf immunotherapies for a range of pathologies including cancer. I aimed to identify pan-cancer targeting γδ T-cells, describe their TCRs and discover the ligands they use to recognise such a wide range of targets. Results: I used herpesvirus infected cells to prime and isolate rare, tumour reactive γδ T-cell lines from three healthy donors. An interesting T-cell clone from each individual was subjected to novel technologies to find the TCR ligand. A whole genome CRISPR/Cas9 library screen determined that tumour recognition by one clone required that transformed cells express SCNN1A, a key component of the major epithelial sodium transporter. Surprisingly, CRIPSR gene editing and lentiviral transduction technologies demonstrated that the two other clones recognised allogeneic HLA class II alleles expressed on tumour cells. Conclusions: My results offer opportunities for broad-ranging cancer immunotherapies that are HLA-independent and could be applied in all individuals. My discovery that γδ T-cells can recognise allogeneic HLA alleles also serves as a cautionary note to those wishing to apply therapeutic approaches via allogeneic γδ T-cells. My results blur the boundaries between conventional αβ T-cell recognition of peptide-HLA and the ‘unconventional’ γδ T-cell subset that are often currently believed to be blind to HLA. These findings will be of major interest to the γδ T-cell field and should serve as important milestone to future studies of HLA-restricted and non-HLA restricted γδ T-cells.
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