ArticleFrontiers in immunology2020
Comparison of a Novel Bisphosphonate Prodrug and Zoledronic Acid in the Induction of Cytotoxicity in Human Vγ2Vδ2 T Cells.
Article in Frontiers in immunology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 21 citations in OpenAlex.
- Article
- Expansion strategies for Vδ2 γδT cells in cancer immunotherapy: Activation, cytokines, and culture conditions.World journal of clinical oncology · 2025Review
- Phosphonodiamidate prodrugs of phosphoantigens (ProPAgens) exhibit potent Vγ9/Vδ2 T cell activation and eradication of cancer cells.RSC medicinal chemistry · 2024Article
- Human Vγ9Vδ2 T cells exhibit antifungal activity againstMicrobiology spectrum · 2024Article
- Article
- Landscape of unconventional γδ T cell subsets in cancer.Molecular biology reports · 2024Review
- Controversial role of γδ T cells in colorectal cancer.American journal of cancer research · 2024Review
- Advancements in γδT cell engineering: paving the way for enhanced cancer immunotherapy.Frontiers in immunology · 2024Review
- B7H3-targeting chimeric antigen receptor modification enhances antitumor effect of Vγ9Vδ2 T cells in glioblastoma.Journal of translational medicine · 2023Article
- Targeting Melanoma-Associated Fibroblasts (MAFs) with Activated γδ (Vδ2) T Cells: An In Vitro Cytotoxicity Model.International journal of molecular sciences · 2023Article
- Human γδ T cells induce CD8Cancer immunology, immunotherapy : CII · 2023Article
- Vγ9Vδ2 T-cell immunotherapy in blood cancers: ready for prime time?Frontiers in immunology · 2023Review
- Three distinct mechanisms underlying human γδ T cell-mediated cytotoxicity against malignant pleural mesothelioma.Frontiers in immunology · 2023Article
- EBV latent membrane protein 1 augments γδ T cell cytotoxicity against nasopharyngeal carcinoma by induction of butyrophilin molecules.Theranostics · 2023Article
- Two Distinct Mechanisms Underlying γδ T Cell-Mediated Regulation of Collagen Type I in Lung Fibroblasts.Cells · 2022Article
- Prodrugs of pyrophosphates and bisphosphonates: disguising phosphorus oxyanions.RSC medicinal chemistry · 2022Review
- Osteoclasts adapt to physioxia perturbation through DNA demethylation.EMBO reports · 2021Article
- Phosphonate and Bisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthases: A Structure-Guided Perspective.Frontiers in chemistry · 2020Review
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
Abstract
Increasing attention has been paid to human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) in the field of cancer immunotherapy. We have previously demonstrated that a novel bisphosphonate prodrug, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA), efficiently expands peripheral blood Vγ2Vδ2 T cells to purities up to 95-99% in 10-11 days. In the present study, we first examined the effect of PTA on farnesyl diphosphate synthase (FDPS) using liquid chromatography mass spectrometry (LC-MS) to analyze the mechanism underlying the PTA-mediated expansion of Vγ2Vδ2 T cells. We find that the prodrug induced the accumulation of both isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), direct upstream metabolites of FDPS. This indicates that not only IPP but also DMAPP plays an important role in PTA-mediated stimulation of Vγ2Vδ2 T cells. We next analyzed TCR-independent cytotoxicity of Vγ2Vδ2 T cells. When human lung cancer cell lines were challenged by Vγ2Vδ2 T cells, no detectable cytotoxicity was observed in 40 min. The lung cancer cell lines were, however, significantly killed by Vγ2Vδ2 T cells after 4-16 h in an effector-to-target ratio-dependent manner, demonstrating that Vγ2Vδ2 T cell-based cell therapy required a large number of cells and longer time when tumor cells were not sensitized. By contrast, pulsing tumor cell lines with 10-30 nM of PTA induced significant lysis of tumor cells by Vγ2Vδ2 T cells even in 40 min. Similar levels of cytotoxicity were elicited by ZOL at concentrations of 100-300 μM, which were much higher than blood levels of ZOL after infusion (1-2 μM), suggesting that standard 4 mg infusion of ZOL was not enough to sensitize lung cancer cells in clinical settings. In addition, Vγ2Vδ2 T cells secreted interferon-γ (IFN-γ) when challenged by lung cancer cell lines pulsed with PTA in a dose-dependent manner. Taken together, PTA could be utilized for both expansion of Vγ2Vδ2 T cells
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