{"doi":"10.3389/fimmu.2024.1414812","title":"Editorial: Optimized gene-engineering and combination therapies to boost γδT cell immunotherapeutic performance","abstract":"leukaemia types or solid tumours. Additionally, the major histocompatibility complex (MHC) recognition-driven alloreactivity of peripheral αβT cells has restricted their use predominantly to autologous adoptive transfer, which is accompanied by high cost and complex logistics of product manufacture 4 . γδT cells, natural killer T cells (NKT) and NK cells are all alternative cytotoxic lymphocyte (CTL) sources that are MHC non-restricted and do not cause graft versus host disease (GvHD). All are further easily accessible in the peripheral blood of healthy donors, from which they can be expanded and genetically modified using GMP-compatible methods.γδT cells offer a particularly attractive route for cellular immunotherapy development, as their phenotype combines features of a range of the afore-mentioned cells. Like classical αβT cells as well as NKT cells, γδT cells express a T cell receptor (TCR). What defines the γδT cell subset is its expression of TCRγ/δ as opposed to TCRα/β heterodimers. While different TCRγ/δ clones have been found to engage various atypical MHCs loaded with sulfatide or lipid antigens, as well as butyrophilin and butyrophilin-like molecules, TCRγ/δ biology and ligand recognition remain poorly understood 5 .In addition to the TCR, γδT cells express a range of receptors that are also expressed by NK cells. These are activated by ligand patterns of cellular stress and transformation, and include NKG2D, DNAM-1, NKp30 and NKp44. Both NK and γδT cells can further express receptors that engage humoral immunity, including Fc receptor CD16. Upon target engagement, human γδT cells can exhibit prolific Th1-type cytokine production and cytotoxicity. Murine γδT cells further appear to present with a thymically-determined Th1 / Th17 functional dichotomy characterised by IFN-γ and IL-17 production, respectively, though the degree to which this is relevant for primate γδT cell biology remains unknown 6 .tumour functionality in their article on Vγ9Vδ2 cell tumour antigen cross-presentation to αβT cells 7 . Vγ9Vδ2 cells are the most common peripheral γδT cell subset, and their ability to cross-present antigens has been described in several contexts 8,9 . This unique aspect of their biology represents a significant additional route of immune response modulation that γδT cells possess in contrast to αβT cells or NK cells. The most sizeable portion of the collection focuses on pre-clinical data reports that examine γδT cell therapeutic combinations. In all cases, the type of γδT cell discussed is the peripherally-dominant Vγ9Vδ2 subset. Mei-Ling Lou and colleagues describe a novel approach to modulating TCR engagement by increasing tumour cell accumulation of the Vγ9Vδ2-TCR ligand, isopentenyl pyrophosphate (IPP) 13 . They achieved this by knocking out the IPP-catalyzing enzyme, farnesyl diphosphate synthase, using short-hairpin RNA. This work is followed by a range of studies examining Vγ9Vδ2 cell checkpoint receptor expression and blockade, with a compelling if complex set of results. Laura A. Ridgley and team examined Vγ9Vδ2 T cell checkpoint receptor expression following phosphoantigen challenge, and found that, in the context of their THP-1 acute myeloid leukaemia model, TIM-3, LAG-3 and NKG2A, but not PD-1, were promising targets for checkpoint blockade 14 . Curiously, however, they reported that -despite the substantial upregulation of these receptors upon T cell challenge -the team were unable to identify a cytotoxic or cytokine benefit of applying checkpoint blockers, speculating instead that these may play a more important role in de-repressing T cell proliferation. This was in some contrast to a report by Lui and colleagues, where PD-1 blockade was efficacious at enhancing Vγ9Vδ2 cell immunotherapy against mesothelioma in vitro and in vivo, especially against PD-L1 high tumours, but not in a manner that was dependent on pyroptosis 15 . Claudia Gianotta et al, meanwhile, reported that, in the context of multiple mye","journal":"Frontiers in Immunology","year":2024,"id":496764,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":255129,"name":"Daniel Abate‐Daga","orcid":"0000-0002-2571-0215","position":1,"is_corresponding":false},{"id":1343317,"name":"Jonathan Fisher","orcid":"0000-0003-3302-2241","position":2,"is_corresponding":false},{"id":1343316,"name":"Marta Barisa","orcid":"0000-0001-7846-6810","position":0,"is_corresponding":true}],"reference_count":8,"raw_metadata":null,"created_at":"2026-07-19T02:09:27.134858Z","pmid":"38698854","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}