In vivo phosphoantigen levels in bisphosphonate-treated human breast tumors trigger Vγ9Vδ2 T-cell antitumor cytotoxicity through ICAM-1 engagement

Clin Cancer Res. 2012 Nov 15;18(22):6249-59. doi: 10.1158/1078-0432.CCR-12-0918. Epub 2012 Oct 2.


Purpose: 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.

Experimental design: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • Antigens, Neoplasm / metabolism*
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / immunology
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cytotoxicity, Immunologic / drug effects
  • Etidronic Acid / analogs & derivatives*
  • Etidronic Acid / pharmacology
  • Female
  • Geranyltranstransferase / metabolism
  • Hemiterpenes / immunology
  • Hemiterpenes / metabolism
  • Humans
  • Immunologic Factors / pharmacology
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Leukocytes, Mononuclear / drug effects
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Organophosphorus Compounds / immunology
  • Organophosphorus Compounds / metabolism
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • Risedronic Acid
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism*
  • Xenograft Model Antitumor Assays


  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Hemiterpenes
  • Immunologic Factors
  • Organophosphorus Compounds
  • Receptors, Antigen, T-Cell, gamma-delta
  • Intercellular Adhesion Molecule-1
  • isopentenyl pyrophosphate
  • Geranyltranstransferase
  • Risedronic Acid
  • Etidronic Acid