Comparison of γδ T cell responses and farnesyl diphosphate synthase inhibition in tumor cells pretreated with zoledronic acid.

Abstract

Exposing human tumor cells to nitrogen-containing bisphosphonates, such as zoledronic acid (Zol), greatly increases their susceptibility to killing by γδ T cells. Based on this finding and other studies, cancer immunotherapy using γδ T cells and nitrogen-containing bisphosphonates has been studied in pilot clinical trials and has shown benefits. Although Zol treatment can render a wide variety of human tumor cells susceptible to γδ T cell killing, there has not been a systematic investigation to determine which types of tumor cells are the most susceptible to γδ T cell-mediated cytotoxicity. In this study, we determined the Zol concentrations required to stimulate half maximal tumor necrosis factor-α production by γδ T cells cultured with various tumor cell lines pretreated with Zol and compared these concentrations with those required for half maximal inhibition of farnesyl diphosphate synthase (FPPS) in the same tumor cell lines. The inhibition of tumor cell growth by Zol was also assessed. We found that FPPS inhibition strongly correlated with γδ T cell activation, confirming that the mechanism underlying γδ T cell activation by Zol is isopentenyl diphosphate (IPP) accumulation due to FPPS blockade. In addition, we showed that γδ T-cell receptor-mediated signaling correlated with γδ T cell tumor necrosis factor-α production and cytotoxicity. Some lymphoma, myeloid leukemia, and mammary carcinoma cell lines were relatively resistant to Zol treatment, suggesting that assessing tumor sensitivity to Zol may help select those patients most likely to benefit from immunotherapy with γδ T cells.

• Authors: Atif S M Idrees, Tomoharu Sugie, Chiyomi Inoue, Kaoru Murata-Hirai, Haruki Okamura, Craig T Morita, Nagahiro Minato, Masakazu Toi, Yoshimasa Tanaka
• Journal: Cancer science (Cancer Sci) Vol. 104 Issue 5 Pg. 536-42 (May 2013) ISSN: 1349-7006 [Electronic] England
• PMID: 23387443 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2013 Japanese Cancer Association.

Chemical References

• Diphosphonates
• Hemiterpenes
• Imidazoles
• Organophosphorus Compounds
• Receptors, Antigen, T-Cell, gamma-delta
• Tumor Necrosis Factor-alpha
• isopentenyl pyrophosphate
• Zoledronic Acid
• Geranyltranstransferase

Topics

• Cell Line, Tumor
• Cytotoxicity, Immunologic (drug effects, immunology)
• Diphosphonates (immunology, pharmacology)
• Geranyltranstransferase (antagonists & inhibitors, immunology, metabolism)
• HL-60 Cells
• Hemiterpenes (immunology, metabolism)
• Humans
• Imidazoles (immunology, pharmacology)
• K562 Cells
• Leukemia, Myeloid (drug therapy, immunology, metabolism)
• Lymphoma (drug therapy, immunology, metabolism)
• MCF-7 Cells
• Organophosphorus Compounds (immunology, metabolism)
• Receptors, Antigen, T-Cell, gamma-delta (immunology, metabolism)
• T-Lymphocytes (drug effects, immunology)
• Tumor Necrosis Factor-alpha (immunology, metabolism)
• U937 Cells
• Zoledronic Acid