Human gamma delta T cells: from fundamental biology to cancer immunotherapy

Gamma-delta T-cells are an understudied, unconventional lineage of immunocytes conserved throughout 500-million years of vertebrate evolution. These cells are strikingly associated with barrier tissues from which most solid tumours arise. Together, these attributes imply important and non-redundant contributions to tissue/tumour immunosurveillance. Indeed, we have shown that human gamma-delta T-cells are potently tumouricidal in vitro and their presence predicts favourable cancer outcomes. Nonetheless, clinical trials utilising gamma-delta T-cells in solid cancers have demonstrated poor efficacy, likely reflecting our limited understanding of the cells’ biology in situ within the tissue/tumour microenvironment (TME). Building on previous findings in vitro, we will utilise high-definition spatial transcriptomics in combination with functional immunoassays on surgically resected tissues/tumours to reveal the localisation of gamma-delta T-cells, their cell- cell interactions, and the molecular switches underpinning their functions in situ. Contextualisation with clinicopathological metrics will establish correlates of notable clinical outcomes (e.g., survival, therapy response). By combining a priori knowledge with unbiased approaches, we will highlight putative functional axes governing gamma-delta biology within the TME. These will be tested in vitro by tractable immunoassays and functional genomics screens using patient-derived model systems. In later years we will translate our work for patient-benefit through establishing real-world clinical relevance and proof-of-concept therapies.