The promise of γδ T cells and the γδ T cell receptor for cancer immunotherapy

gamma delta T cells form an important part of adaptive immune responses against infections and malignant transformation. The molecular targets of human gamma delta T cell receptors (TCRs) remain largely unknown, but recent studies have confirmed the recognition of phosphorylated prenyl metabolites, lipids in complex with CD1 molecules and markers of cellular stress. All of these molecules are upregulated on various cancer types, highlighting the potential importance of the gamma delta T cell compartment in cancer immunosurveillance and paving the way for the use of gamma delta TCRs in cancer therapy. Ligand recognition by the gamma delta TCR often requires accessory/co-stimulatory stress molecules on both T cells and target cells; this cellular stress context therefore provides a failsafe against harmful self-reactivity. Unlike alpha beta T cells, gamma delta T cells recognise their targets irrespective of HLA haplotype and therefore offer exciting possibilities for off-the-shelf, pan-population cancer immunotherapies. Here, we present a review of known ligands of human gamma delta T cells and discuss the promise of harnessing these cells for cancer treatment.