High Phosphoantigen Levels in Bisphosphonate-Treated Human Breast Tumors Promote Vγ9Vδ2 T-Cell Chemotaxis and Cytotoxicity In Vivo

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 V gamma 9V delta 2 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 V gamma 9V delta 2 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 V gamma 9V delta 2 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, V gamma 9V delta 2 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 V gamma 9V delta 2 T-cell chemotaxis to the tumor. Without V gamma 9V delta 2 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 V gamma 9V delta 2 T-cell-mediated immunotherapy. Cancer Res; 71(13); 4562-72. (C) 2011 AACR.