Local γδ T cells: translating promise to practice in cancer immunotherapy

Rapid bench-to-bedside translation of basic immunology to cancer immunotherapy has revolutionised the clinical practice of oncology over the last decade. Immune checkpoint inhibitors targeting alpha beta T cells now offer durable remissions and even cures for some patients with hitherto treatment-refractory metastatic cancers. Unfortunately, these treatments only benefit a minority of patients and efforts to improve efficacy through combination therapies utilising alpha beta T cells have seen diminishing returns. Alongside alpha beta T cells and B cells, gamma delta T cells are a third lineage of adaptive lymphocytes. Less is known about these cells, and they remain relatively untested in cancer immunotherapy. Whilst preclinical evidence supports their utility, the few early-phase trials involving gamma delta T cells have failed to demonstrate convincing efficacy in solid cancers. Here we review recent progress in our understanding of how these cells are regulated, especially locally within tissues, and the potential for translation. In particular, we focus on the latest advances in the field of butyrophilin (BTN) and BTN-like (BTNL) regulation of gamma delta T cells and speculate on how these advances may address the limitations of historical approaches in utilising these cells, as well as how they may inform novel approaches in deploying these cells for cancer immunotherapy.