RRC ID 61441
Author Idrees AS, Sugie T, Inoue C, Murata-Hirai K, Okamura H, Morita CT, Minato N, Toi M, Tanaka Y.
Title Comparison of γδ T cell responses and farnesyl diphosphate synthase inhibition in tumor cells pretreated with zoledronic acid.
Journal Cancer Sci
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.
Volume 104(5)
Pages 536-42
Published 2013-5-1
DOI 10.1111/cas.12124
PMID 23387443
PMC PMC3755363
MeSH Cell Line, Tumor Cytotoxicity, Immunologic / drug effects Cytotoxicity, Immunologic / immunology Diphosphonates / immunology Diphosphonates / pharmacology* Geranyltranstransferase / antagonists & inhibitors* Geranyltranstransferase / immunology Geranyltranstransferase / metabolism HL-60 Cells Hemiterpenes / immunology Hemiterpenes / metabolism Humans Imidazoles / immunology Imidazoles / pharmacology* K562 Cells Leukemia, Myeloid / drug therapy* Leukemia, Myeloid / immunology Leukemia, Myeloid / metabolism Lymphoma / drug therapy* Lymphoma / immunology Lymphoma / metabolism MCF-7 Cells Organophosphorus Compounds / immunology Organophosphorus Compounds / metabolism Receptors, Antigen, T-Cell, gamma-delta / immunology* Receptors, Antigen, T-Cell, gamma-delta / metabolism T-Lymphocytes / drug effects* T-Lymphocytes / immunology Tumor Necrosis Factor-alpha / immunology Tumor Necrosis Factor-alpha / metabolism U937 Cells Zoledronic Acid
IF 4.966
Human and Animal Cells TGBC1TKB(RCB1129) TGBC24TKB(RCB1196)