Editorial : Next generation γδ T cell-based tumor immunotherapy

The discovery of the γδ T-cell receptor (TCR) and its ability to confer potent cytotoxic activity in CD3+ cells some 35 years ago sparked the initial proliferation in research that garnered widespread interest in the biology and function of γδ T cells. The identification of major human γδ TCR clonotypes, their tissue distributions as well as dynamic changes throughout ontogeny and in disease states have contributed to the appreciation of human γδ T cell diversity. Despite this, incomplete understanding of mechanisms underlying the complexity of various γδ T cell subsets in homeostasis, inflammation and malignancy restricted the focus of most early studies to blood circulating Vγ9Vδ2 T cells which could be robustly activated and expanded ex vivo using aminobisphosphonates such as zoledronate compared with other γδ T cell subsets for which activating ligands were then largely unknown. This galvanized attempts to harness the tumoricidal potential of Vγ9Vδ2 T cells in clinical trials. Although these cells exhibited highly promising safety profiles in patients, early trial data revealed suboptimal anti-tumor efficacy. Despite these setbacks, recent breakthroughs in deciphering the unique antigen (Ag) binding modes of γδ TCR coupled with high dimensional analyses of tissue- and disease-specific γδ T cell subsets at single cell resolution led to renewed excitement in the development of γδ T cell-based therapeutics. This Research Topic has compiled a series of nine articles of which five review our hitherto understanding of the multifaceted nature of γδ T cells and four report original research providing new insights into the molecular and cellular regulation of a diverse repertoire of γδ T cells, paving the way for next generation γδ T cell-based tumor immunotherapies.


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