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Comparison of a Novel Bisphosphonate Prodrug and Zoledronic Acid in the Induction of Cytotoxicity in Human Vγ2Vδ2 T Cells


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Title: Comparison of a Novel Bisphosphonate Prodrug and Zoledronic Acid in the Induction of Cytotoxicity in Human Vγ2Vδ2 T Cells
Authors: Okuno, Daisuke / Sugiura, Yuki / Sakamoto, Noriho / Tagod, Mohammed S. O. / Iwasaki, Masashi / Noda, Shuto / Tamura, Akihiro / Senju, Hiroaki / Umeyama, Yasuhiro / Yamaguchi, Hiroyuki / Suematsu, Makoto / Morita, Craig T. / Tanaka, Yoshimasa / Mukae, Hiroshi
Issue Date: 21-Jul-2020
Publisher: Frontiers Media S.A.
Citation: Frontiers in Immunology, 11, art.no.1405; 2020
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 ex vivo and sensitization of tumor cells in vivo in Vγ2Vδ2 T cell-based cancer immunotherapy. For use in patients, further studies on drug delivery are essential because of the hydrophobic nature of the prodrug.
Keywords: bisphosphonate / cytotoxicity / mass spectroscopy / prodrug / Vγ2Vδ2 T cells
URI: http://hdl.handle.net/10069/40229
DOI: 10.3389/fimmu.2020.01405
Rights: © 2020 Okuno, Sugiura, Sakamoto, Tagod, Iwasaki, Noda, Tamura, Senju, Umeyama, Yamaguchi, Suematsu, Morita, Tanaka and Mukae. This is an openaccess article distributed under the terms of the Creative Commons AttributionLicense (CC BY). The use, distribution or reproduction in other forums is permitted,provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Type: Journal Article
Text Version: publisher
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/40229

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