AUTHOR=Saura-Esteller José , de Jong Milon , King Lisa A. , Ensing Erik , Winograd Benjamin , de Gruijl Tanja D. , Parren Paul W. H. I. , van der Vliet Hans J. 

TITLE=Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.915837

DOI=10.3389/fimmu.2022.915837

ISSN=1664-3224

ABSTRACT=gd T-cells directly recognize and kill transformed cells independently of HLA-antigen presentation, which makes them a highly promising effector cell compartment for cancer immunotherapy Novel gd T-cell-based immunotherapies, primarily focusing on the two major gd T-cell subtypes that infiltrate tumors (i.e. Vd1 and Vd2), are being developed. The Vd1 T-cell subset is enriched in tissues and contains both effector T-cells as well as regulatory T-cells with tumor-promoting potential. Vd2 T-cells, in contrast, are enriched in circulation and consist of a large, relatively homogeneous, pro-inflammatory effector T-cell subset. Healthy individuals typically harbor in the order of 50-500 million Vg9Vd2 T-cells in the peripheral blood alone (1-10% of the total CD3+ T-cell population), which can rapidly expand upon stimulation. 
The Vg9Vd2 T-cell receptor senses intracellular phosphorylated metabolites, which accumulate in cancer cells as a result of mevalonate pathway dysregulation or upon pharmaceutical intervention. Early clinical studies investigating the therapeutic potential of Vg9Vd2 T-cells were based on either ex vivo expansion and adoptive transfer or their systemic activation with aminobisphosphonates or synthetic phosphoantigens, either alone or combined with low dose IL-2. Immune-related adverse events (irAE) were generally mild, but the clinical efficacy of these approaches provided overall limited benefit. In recent years, critical advances have renewed the excitement for the potential of Vg9Vd2 T-cells in cancer immunotherapy.
Here, we review gd T-cell-based therapeutic strategies and discuss the prospects of those currently evaluated in clinical studies in cancer patients as well as future therapies that might arise from current promising pre-clinical results.