Comparison of a Novel Bisphosphonate Prodrug and Zoledronic Acid in the Induction of Cytotoxicity in Human Vγ2Vδ2 T Cells.
Antineoplastic Agents
/ pharmacology
Cytotoxicity, Immunologic
/ drug effects
Diphosphonates
/ pharmacology
Humans
Immunotherapy
/ methods
Lymphocyte Activation
/ drug effects
Prodrugs
/ pharmacology
Receptors, Antigen, T-Cell, gamma-delta
/ immunology
T-Lymphocytes
/ drug effects
Zoledronic Acid
/ pharmacology
Vγ2Vδ2 T cells
bisphosphonate
cytotoxicity
mass spectroscopy
prodrug
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2020
2020
Historique:
received:
19
02
2020
accepted:
01
06
2020
entrez:
15
8
2020
pubmed:
15
8
2020
medline:
7
4
2021
Statut:
epublish
Résumé
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
Identifiants
pubmed: 32793196
doi: 10.3389/fimmu.2020.01405
pmc: PMC7385076
doi:
Substances chimiques
Antineoplastic Agents
0
Diphosphonates
0
Prodrugs
0
Receptors, Antigen, T-Cell, gamma-delta
0
Zoledronic Acid
6XC1PAD3KF
Types de publication
Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1405Subventions
Organisme : BLRD VA
ID : I01 BX000972
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA086862
Pays : United States
Informations de copyright
Copyright © 2020 Okuno, Sugiura, Sakamoto, Tagod, Iwasaki, Noda, Tamura, Senju, Umeyama, Yamaguchi, Suematsu, Morita, Tanaka and Mukae.
Références
ChemMedChem. 2016 Dec 16;11(24):2656-2663
pubmed: 27786425
Sci Rep. 2017 Jul 20;7(1):5987
pubmed: 28729550
Semin Cell Dev Biol. 2018 Dec;84:65-74
pubmed: 29471037
Cell Rep. 2016 May 31;15(9):1973-85
pubmed: 27210746
ACS Chem Biol. 2017 Oct 20;12(10):2631-2643
pubmed: 28862425
Blood. 2003 Jul 1;102(1):200-6
pubmed: 12623838
Cancer Res. 2007 Aug 1;67(15):7450-7
pubmed: 17671215
Immunity. 2019 Apr 16;50(4):1043-1053.e5
pubmed: 30902636
J Immunol. 2001 May 1;166(9):5508-14
pubmed: 11313389
Cancer Sci. 2018 Mar;109(3):587-599
pubmed: 29288540
Science. 2001 Jan 12;291(5502):319-22
pubmed: 11209085
Clin Immunol. 2016 Nov;172:90-97
pubmed: 27444042
J Transl Med. 2014 Feb 15;12:45
pubmed: 24528541
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12108-13
pubmed: 12198182
Curr Pharm Des. 2010;16(27):2961-9
pubmed: 20722615
Proc Natl Acad Sci U S A. 2017 Aug 29;114(35):E7311-E7320
pubmed: 28807997
Science. 1994 Apr 8;264(5156):267-70
pubmed: 8146660
Br J Haematol. 2009 Jan;144(2):245-50
pubmed: 19016713
Annu Rev Immunol. 2015;33:169-200
pubmed: 25493333
Blood. 2006 Jan 15;107(2):651-4
pubmed: 16179378
Arch Biochem Biophys. 2000 Jan 1;373(1):231-41
pubmed: 10620343
J Exp Med. 2003 Jan 20;197(2):163-8
pubmed: 12538656
J Immunol. 2013 Aug 1;191(3):1029-42
pubmed: 23833237
N Engl J Med. 2012 Jun 28;366(26):2455-65
pubmed: 22658128
Int J Cancer. 2004 Dec 10;112(5):727-32
pubmed: 15386388
J Med Chem. 2006 Sep 21;49(19):5804-14
pubmed: 16970405
J Clin Pharmacol. 2003 Feb;43(2):154-62
pubmed: 12616668
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12293-7
pubmed: 12218188
J Biol Chem. 2010 Jan 15;285(3):1967-79
pubmed: 19875454
Cancer Res. 2007 Jan 1;67(1):5-8
pubmed: 17210676
Int J Biol Sci. 2018 Mar 9;14(3):331-340
pubmed: 29559850
N Engl J Med. 2012 Jun 28;366(26):2443-54
pubmed: 22658127
Biochem Biophys Res Commun. 1999 Feb 16;255(2):491-4
pubmed: 10049736
ChemMedChem. 2017 Dec 7;12(23):2006-2013
pubmed: 29110403
Blood. 2011 Sep 8;118(10):2743-51
pubmed: 21673342
Blood. 2010 Sep 9;116(10):1726-33
pubmed: 20519625
Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4712-7
pubmed: 12682289
Nat Med. 2003 Dec;9(12):1477-83
pubmed: 14595408
FEBS Lett. 2001 Dec 7;509(2):317-22
pubmed: 11741609
Mol Pharmacol. 2006 May;69(5):1624-32
pubmed: 16501031
Immunity. 2014 Apr 17;40(4):490-500
pubmed: 24703779
J Immunother Cancer. 2017 Feb 21;5:9
pubmed: 28239463
Nat Med. 2019 Jan;25(1):89-94
pubmed: 30510250
Anal Chem. 2015 Jun 16;87(12):6371-9
pubmed: 25973679
Cancer Immunol Immunother. 2020 Sep;69(9):1699-1712
pubmed: 32333080
Science. 2020 Feb 7;367(6478):
pubmed: 31919129
J Immunol. 1995 Feb 1;154(3):998-1006
pubmed: 7529807
Cancer Immunol Immunother. 2011 Aug;60(8):1075-84
pubmed: 21519826
Biochem Biophys Res Commun. 2016 Sep 23;478(3):1298-303
pubmed: 27553282
Nat Immunol. 2019 Feb;20(2):121-128
pubmed: 30664765
J Immunol. 2019 Aug 1;203(3):607-626
pubmed: 31227581
Blood. 2012 Sep 13;120(11):2269-79
pubmed: 22767497
J Immunol. 2001 Nov 1;167(9):5092-8
pubmed: 11673519
Proc Natl Acad Sci U S A. 2018 Jan 30;115(5):1039-1044
pubmed: 29339503
Nature. 1995 May 11;375(6527):155-8
pubmed: 7753173
J Immunol. 2004 Oct 15;173(8):4936-44
pubmed: 15470035
J Immunol Methods. 1984 Aug 3;72(1):219-27
pubmed: 6086760