Cancer Therapy: Preclinical In Vivo Phosphoantigen Levels in Bisphosphonate-Treated Human Breast Tumors Trigger Vg9Vd2 T-cell Antitumor Cytotoxicity through ICAM-1 Engagement

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 Vg9Vd2 T cells. However, mechanisms responsible for Vg9Vd2 T-cell recognition of N-BP–treated tumors producing IPP/ApppI remain unclear. Experimental Design: The effects of N-BPs on Vg9Vd2 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 Vg9Vd2 T cells in N-BP–treated animals were also examined. Results: We found a strong correlation between Vg9Vd2 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 Vg9Vd2 T cells infiltrated and inhibited growthof tumors that producedhigh IPP/ApppI levels but not those expressing low IPP/ApppI levels. The combination of doxorubicin with a N-BP improved, however, Vg9Vd2 T-cell cytotoxicity against breast tumors expressing low IPP/ApppI levels. Moreover, Vg9Vd2 T-cell cytotoxicity inmice 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 Vg9Vd2 T cells in vivo. Conclusion: These findings suggest that N-BPs can have an adjuvant role in cancer therapy by activating Vg9Vd2 T-cell cytotoxicity in patients with breast cancer that produces high IPP/ApppI levels after N-BP treatment. Clin Cancer Res; 18(22); 6249–59. 2012 AACR.