In vivo phosphoantigen levels in bisphosphonate-treated human breast tumors trigger Vγ9Vδ2 T-cell antitumor cytotoxicity through ICAM-1 engagement.

Abstract

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 Vγ9Vδ2 T cells. However, mechanisms responsible for Vγ9Vδ2 T-cell recognition of N-BP-treated tumors producing IPP/ApppI remain unclear.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Ismahène Benzaïd, Hannu Mönkkönen, Edith Bonnelye, Jukka Mönkkönen, Philippe Clézardin
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 22 Pg. 6249-59 (Nov 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 23032740 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Antigens, Neoplasm
• Antineoplastic Agents
• Hemiterpenes
• Immunologic Factors
• Organophosphorus Compounds
• Receptors, Antigen, T-Cell, gamma-delta
• Intercellular Adhesion Molecule-1
• isopentenyl pyrophosphate
• Geranyltranstransferase
• Risedronic Acid
• Etidronic Acid

Topics

• Animals
• Antigens, Neoplasm (immunology, metabolism)
• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (drug therapy, immunology, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cytotoxicity, Immunologic (drug effects)
• Etidronic Acid (analogs & derivatives, pharmacology)
• Female
• Geranyltranstransferase (metabolism)
• Hemiterpenes (immunology, metabolism)
• Humans
• Immunologic Factors (pharmacology)
• Intercellular Adhesion Molecule-1 (metabolism)
• Leukocytes, Mononuclear (drug effects)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Organophosphorus Compounds (immunology, metabolism)
• Receptors, Antigen, T-Cell, gamma-delta (metabolism)
• Risedronic Acid
• T-Lymphocytes, Cytotoxic (drug effects, immunology, metabolism)
• Xenograft Model Antitumor Assays