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: Ismahène Benzaïd, Hannu Mönkkönen, Verena Stresing, Edith Bonnelye, Jonathan Green, Jukka Mönkkönen, Jean-Louis Touraine, Philippe Clézardin
• Journal: Cancer research (Cancer Res) Vol. 71 Issue 13 Pg. 4562-72 (Jul 01 2011) ISSN: 1538-7445 [Electronic] United States
• PMID: 21646473 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Antigens, Neoplasm
• Diphosphonates
• Hemiterpenes
• Imidazoles
• Organophosphorus Compounds
• Receptors, Antigen, T-Cell, gamma-delta
• triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester
• isopentenyl pyrophosphate
• Zoledronic Acid
• Adenosine Triphosphate

Topics

• Adenosine Triphosphate (analogs & derivatives, metabolism)
• Animals
• Antigens, Neoplasm (immunology, metabolism)
• Breast Neoplasms (drug therapy, immunology, metabolism)
• Cell Line, Tumor
• Cytotoxicity, Immunologic
• Diphosphonates (pharmacology)
• Female
• Hemiterpenes (metabolism)
• Humans
• Imidazoles (pharmacology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Organophosphorus Compounds (metabolism)
• Phosphorylation
• Receptors, Antigen, T-Cell, gamma-delta (immunology)
• T-Lymphocytes (drug effects, immunology)
• Zoledronic Acid