title: Comparison of γδ T cell responses and farnesyl diphosphate synthase inhibition in tumor cells pretreated with zoledronic acid.
abstract: Exposing human tumor cells to nitrogen-containing bisphosphonates, such as zoledronic acid (Zol), greatly increases their susceptibility to killing by γδ T cells. Based on this finding and other studies, cancer immunotherapy using γδ T cells and nitrogen-containing bisphosphonates has been studied in pilot clinical trials and has shown benefits. Although Zol treatment can render a wide variety of human tumor cells susceptible to γδ T cell killing, there has not been a systematic investigation to determine which types of tumor cells are the most susceptible to γδ T cell-mediated cytotoxicity. In this study, we determined the Zol concentrations required to stimulate half maximal tumor necrosis factor-α production by γδ T cells cultured with various tumor cell lines pretreated with Zol and compared these concentrations with those required for half maximal inhibition of farnesyl diphosphate synthase (FPPS) in the same tumor cell lines. The inhibition of tumor cell growth by Zol was also assessed. We found that FPPS inhibition strongly correlated with γδ T cell activation, confirming that the mechanism underlying γδ T cell activation by Zol is isopentenyl diphosphate (IPP) accumulation due to FPPS blockade. In addition, we showed that γδ T-cell receptor-mediated signaling correlated with γδ T cell tumor necrosis factor-α production and cytotoxicity. Some lymphoma, myeloid leukemia, and mammary carcinoma cell lines were relatively resistant to Zol treatment, suggesting that assessing tumor sensitivity to Zol may help select those patients most likely to benefit from immunotherapy with γδ T cells.
authors: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Atif S M
authors: AS
authors: Idrees
authors: Tomoharu
authors: T
authors: Sugie
authors: Chiyomi
authors: C
authors: Inoue
authors: Kaoru
authors: K
authors: Murata-Hirai
authors: Haruki
authors: H
authors: Okamura
authors: Craig T
authors: CT
authors: Morita
authors: Nagahiro
authors: N
authors: Minato
authors: Masakazu
authors: M
authors: Toi
authors: Yoshimasa
authors: Y
authors: Tanaka
mesh_terms: D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D004164:Diphosphonates / Q000276:immunology / Q000494:pharmacology*; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D018922:HL-60 Cells; D045782:Hemiterpenes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000276:immunology / Q000494:pharmacology*; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008223:Lymphoma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D061986:MCF-7 Cells; D009943:Organophosphorus Compounds / Q000276:immunology / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D020298:U937 Cells; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D045782:Hemiterpenes; D007093:Imidazoles; D009943:Organophosphorus Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha; C004809:isopentenyl pyrophosphate; D000077211:Zoledronic Acid; D051228:Geranyltranstransferase
references: Cancer Immunol Immunother. 2011 Oct;60(10):1447-60
references: 21647691
references: Mol Cell Biol. 2002 Feb;22(4):1001-15
references: 11809793
references: J Exp Med. 2003 Jan 20;197(2):163-8
references: 12538656
references: Clin Exp Immunol. 2010 Aug;161(2):290-7
references: 20491785
references: Blood. 2000 Jul 15;96(2):384-92
references: 10887096
references: Eur J Immunol. 2012 Jul;42(7):1668-76
references: 22806069
references: N Engl J Med. 2009 Feb 12;360(7):679-91
references: 19213681
references: J Neurooncol. 2011 Jan;101(2):179-88
references: 20532954
references: Cancer Res. 2011 Jul 1;71(13):4562-72
references: 21646473
references: Br J Cancer. 2011 Sep 6;105(6):778-86
references: 21847128
references: Lancet Oncol. 2011 Jul;12(7):631-41
references: 21641868
references: J Bone Miner Res. 2004 Feb;19(2):278-88
references: 14969398
references: Scand J Immunol. 2007 Aug-Sep;66(2-3):320-8
references: 17635809
references: Clin Adv Hematol Oncol. 2011 Apr;9(4):292-9
references: 21558988
references: J Immunol. 2011 Nov 15;187(10):5099-113
references: 22013129
references: Cancer Res. 2007 Jan 1;67(1):5-8
references: 17210676
references: J Am Chem Soc. 2009 Apr 15;131(14):5153-62
references: 19309137
references: Mol Pharmacol. 2006 May;69(5):1624-32
references: 16501031
references: Immunol Rev. 2007 Feb;215:59-76
references: 17291279
references: Lancet Oncol. 2011 Oct;12(11):991-2
references: 21968221
references: Blood. 2012 Oct 18;120(16):3271-9
references: 22932792
references: Anticancer Res. 2010 Feb;30(2):575-9
references: 20332473
references: Eur J Immunol. 2009 May;39(5):1361-8
references: 19404979
references: Immunity. 2009 Aug 21;31(2):184-96
references: 19699170
references: J Immunol. 1995 Feb 1;154(3):998-1006
references: 7529807
references: Cancer Immunol Immunother. 2013 Apr;62(4):677-87
references: 23151944
references: Lancet. 2010 Dec 11;376(9757):1989-99
references: 21131037
references: Cancer Immunol Immunother. 2011 Aug;60(8):1075-84
references: 21519826
references: Immunol Rev. 2007 Feb;215:89-102
references: 17291281
references: Cancer Res. 2007 Aug 1;67(15):7450-7
references: 17671215
references: Int Immunol. 2003 Nov;15(11):1301-7
references: 14565928
references: Cancer Sci. 2013 May;104(5):536-42
references: 23387443
references: J Immunol. 2011 Aug 15;187(4):1578-90
references: 21753152
references: J Leukoc Biol. 2011 Jan;89(1):75-84
references: 20952657
references: Nat Rev Immunol. 2010 Jul;10(7):467-78
references: 20539306
references: J Immunol. 2001 Nov 1;167(9):5092-8
references: 11673519
references: Ann Oncol. 2013 Feb;24(2):398-405
references: 23047045
references: Angew Chem Int Ed Engl. 2010 Feb 1;49(6):1136-8
references: 20039246
references: Clin Exp Immunol. 2006 Jun;144(3):528-33
references: 16734623
references: N Engl J Med. 2011 Oct 13;365(15):1396-405
references: 21995387
references: Blood. 2003 Sep 15;102(6):2310-1
references: 12959943