In Vivo Phosphoantigen Levels in Bisphosphonate-Treated Human Breast Tumors Trigger Vγ9Vδ2 T-cell Antitumor Cytotoxicity through ICAM-1 Engagement

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...

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Published in:	Clinical cancer research 2012-11, Vol.18 (22), p.6249-6259
Main Authors:	BENZAÏD, Ismahène, MÖNKKÖNEN, Hannu, BONNELYE, Edith, MÖNKKÖNEN, Jukka, CLEZARDIN, Philippe
Format:	Article
Language:	eng
Subjects:	Animals Antigens, Neoplasm - immunology Antigens, Neoplasm - metabolism Antineoplastic agents Antineoplastic Agents - pharmacology Biological and medical sciences 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 Gynecology. Andrology. Obstetrics Hemiterpenes - immunology Hemiterpenes - metabolism Humans Immunologic Factors - pharmacology Intercellular Adhesion Molecule-1 - metabolism Leukocytes, Mononuclear - drug effects Mammary gland diseases Medical sciences Mice Mice, Inbred NOD Mice, SCID Organophosphorus Compounds - immunology Organophosphorus Compounds - metabolism Pharmacology. Drug treatments Receptors, Antigen, T-Cell, gamma-delta - metabolism Risedronate Sodium T-Lymphocytes, Cytotoxic - drug effects T-Lymphocytes, Cytotoxic - immunology T-Lymphocytes, Cytotoxic - metabolism Tumors Xenograft Model Antitumor Assays
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Summary:	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. 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. 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. 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.
ISSN:	1078-0432 1557-3265