title: In vivo phosphoantigen levels in bisphosphonate-treated human breast tumors trigger Vγ9Vδ2 T-cell antitumor cytotoxicity through ICAM-1 engagement.
abstract: OBJECTIVE
  Nitrogen-containing bisphosphonates (N-BP) such as zoledronate and risedronate exhibit antitumor effects. They block the activity of farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway, leading to intracellular accumulation of mevalonate metabolites (IPP/ApppI), which are recognized as tumor phosphoantigens by Vγ9Vδ2 T cells. However, mechanisms responsible for Vγ9Vδ2 T-cell recognition of N-BP-treated tumors producing IPP/ApppI remain unclear.
  
  
  METHODS
  The effects of N-BPs on Vγ9Vδ2 T-cell expansion and anticancer activity were evaluated in vitro and in animal models of human breast cancers. The modalities of recognition of breast tumors by Vγ9Vδ2 T cells in N-BP-treated animals were also examined.
  
  
  RESULTS
  We found a strong correlation between Vγ9Vδ2 T-cell anticancer activity and intracellular accumulation of IPP/ApppI in risedronate-treated breast cancer cells in vitro. In addition, following risedronate treatment of immunodeficient mice bearing human breast tumors, human Vγ9Vδ2 T cells infiltrated and inhibited growth of tumors that produced high IPP/ApppI levels but not those expressing low IPP/ApppI levels. The combination of doxorubicin with a N-BP improved, however, Vγ9Vδ2 T-cell cytotoxicity against breast tumors expressing low IPP/ApppI levels. Moreover, Vγ9Vδ2 T-cell cytotoxicity in mice treated with risedronate or zoledronate did not only depend on IPP/ApppI accumulation in tumors but also on expression of tumor cell surface receptor intercellular adhesion molecule-1 (ICAM-1), which triggered the recognition of N-BP-treated breast cancer cells by Vγ9Vδ2 T cells in vivo.
  
  
  CONCLUSIONS
  These findings suggest that N-BPs can have an adjuvant role in cancer therapy by activating Vγ9Vδ2 T-cell cytotoxicity in patients with breast cancer that produces high IPP/ApppI levels after N-BP treatment.
authors.affiliation: Institut National de la Santé et de la Recherche Medicale, UMR 1033, LabEx DEVweCAN, University of Lyon, Lyon, France.
authors.forename: Ismahène
authors.initials: I
authors.lastname: Benzaïd
authors.forename: Hannu
authors.initials: H
authors.lastname: Mönkkönen
authors.forename: Edith
authors.initials: E
authors.lastname: Bonnelye
authors.forename: Jukka
authors.initials: J
authors.lastname: Mönkkönen
authors.forename: Philippe
authors.initials: P
authors.lastname: Clézardin
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D051228:Geranyltranstransferase / Q000378:metabolism; D045782:Hemiterpenes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009943:Organophosphorus Compounds / Q000276:immunology / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D000068296:Risedronic Acid; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D045782:Hemiterpenes; D007155:Immunologic Factors; D009943:Organophosphorus Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; D018799:Intercellular Adhesion Molecule-1; C004809:isopentenyl pyrophosphate; D051228:Geranyltranstransferase; D000068296:Risedronic Acid; D012968:Etidronic Acid