title: High phosphoantigen levels in bisphosphonate-treated human breast tumors promote Vgamma9Vdelta2 T-cell chemotaxis and cytotoxicity in vivo.
abstract: The nitrogen-containing bisphosphonate zoledronic acid (ZOL), a potent inhibitor of farnesyl pyrophosphate synthase, blocks the mevalonate pathway, leading to intracellular accumulation of isopentenyl pyrophosphate/triphosphoric acid I-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester (IPP/ApppI) mevalonate metabolites. IPP/ApppI accumulation in ZOL-treated cancer cells may be recognized by Vγ9Vδ2 T cells as tumor phosphoantigens in vitro. However, the significance of these findings in vivo remains largely unknown. In this study, we investigated the correlation between the anticancer activities of Vγ9Vδ2 T cells and the intracellular IPP/ApppI levels in ZOL-treated breast cancer cells in vitro and in vivo. We found marked differences in IPP/ApppI production among different human breast cancer cell lines post-ZOL treatment. Coculture with purified human Vγ9Vδ2 T cells led to IPP/ApppI-dependent near-complete killing of ZOL-treated breast cancer cells. In ZOL-treated mice bearing subcutaneous breast cancer xenografts, Vγ9Vδ2 T cells infiltrated and inhibited growth of tumors that produced high IPP/ApppI levels, but not those expressing low IPP/ApppI levels. Moreover, IPP/ApppI not only accumulated in cancer cells but it was also secreted, promoting Vγ9Vδ2 T-cell chemotaxis to the tumor. Without Vγ9Vδ2 T-cell expansion, ZOL did not inhibit tumor growth. These findings suggest that cancers-producing high IPP/ApppI levels after ZOL treatment are most likely to benefit from Vγ9Vδ2 T-cell-mediated immunotherapy.
authors.affiliation: INSERM, UMR 1033, F-69372 Lyon, France.
authors.forename: Ismahène
authors.initials: I
authors.lastname: Benzaïd
authors.forename: Hannu
authors.initials: H
authors.lastname: Mönkkönen
authors.forename: Verena
authors.initials: V
authors.lastname: Stresing
authors.forename: Edith
authors.initials: E
authors.lastname: Bonnelye
authors.forename: Jonathan
authors.initials: J
authors.lastname: Green
authors.forename: Jukka
authors.initials: J
authors.lastname: Mönkkönen
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Touraine
authors.forename: Philippe
authors.initials: P
authors.lastname: Clézardin
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D045782:Hemiterpenes / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009943:Organophosphorus Compounds / Q000378:metabolism; D010766:Phosphorylation; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D000077211:Zoledronic Acid
chemical_list: D000951:Antigens, Neoplasm; D004164:Diphosphonates; D045782:Hemiterpenes; D007093:Imidazoles; D009943:Organophosphorus Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; C543712:triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester; C004809:isopentenyl pyrophosphate; D000077211:Zoledronic Acid; D000255:Adenosine Triphosphate