Data from <i>In Vivo</i> Phosphoantigen Levels in Bisphosphonate-Treated Human Breast Tumors Trigger Vγ9Vδ2 T-cell Antitumor Cytotoxicity through ICAM-1 Engagement

Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> The effects of N-BPs on Vγ9Vδ2 T-cell expansion and anticancer activity were evaluated <i>in vitro</i> 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.</p><p><b>Results:</b> We found a strong correlation between Vγ9Vδ2 T-cell anticancer activity and intracellular accumulation of IPP/ApppI in risedronate-treated breast cancer cells <i>in vitro</i>. 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 <i>in vivo</i>.</p><p><b>Conclusion:</b> 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. <i>Clin Cancer Res; 18(22); 6249–59. ©2012 AACR</i>.</p></div>