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. 2007 Aug;56(8):1285-97.
doi: 10.1007/s00262-007-0279-2. Epub 2007 Jan 31.

Chemotherapy and zoledronate sensitize solid tumour cells to Vgamma9Vdelta2 T cell cytotoxicity

Stephen R Mattarollo  1 , Tony Kenna, Mie Nieda, Andrew J Nicol
Affiliations

Chemotherapy and zoledronate sensitize solid tumour cells to Vgamma9Vdelta2 T cell cytotoxicity

Stephen R Mattarollo et al. Cancer Immunol Immunother. 2007 Aug.

Abstract

Combinations of cellular immune-based therapies with chemotherapy and other antitumour agents may be of significant clinical benefit in the treatment of many forms of cancer VSports手机版. Gamma delta (gammadelta) T cells are of particular interest for use in such combined therapies due to their potent antitumour cytotoxicity and relative ease of generation in vitro. Here, we demonstrate high levels of cytotoxicity against solid tumour-derived cell lines with combination treatment utilizing Vgamma9Vdelta2 T cells, chemotherapeutic agents and the bisphosphonate, zoledronate. Pre-treatment with low concentrations of chemotherapeutic agents or zoledronate sensitized tumour cells to rapid killing by Vgamma9Vdelta2 T cells with levels of cytotoxicity approaching 90%. In addition, zoledronate enhanced the chemotherapy-induced sensitization of tumour cells to Vgamma9Vdelta2 T cell cytotoxicity resulting in almost 100% lysis of tumour targets in some cases. Vgamma9Vdelta2 T cell cytotoxicity was mediated by perforin following TCR-dependent and isoprenoid-mediated recognition of tumour cells. Production of IFN-gamma by Vgamma9Vdelta2 T cells was also induced after exposure to sensitized targets. We conclude that administration of Vgamma9Vdelta2 T cells at suitable intervals after chemotherapy and zoledronate may substantially increase antitumour activities in a range of malignancies. .

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Figures

Fig. 1
Fig. 1
Vγ9Vδ2 T cell-induced apoptosis of Daudi cells sensitized with zoledronate or chemotherapy. a Annexin V and 7-AAD staining of Daudi targets (means ± SEM; n = 3 donors) following 4 h co-culture with Vγ9Vδ2 T cells at an E:T ratio of 5:1, either without (grey bars) or after 24 h pre-treatment of targets with zoledronate (50 μM), doxorubicin (0.5 μM) or vincristine (2.5 nM; black bars). Controls of target cell death caused by drug treatment alone are represented by white bars. b Annexin V/7-AAD assay plots showing Annexin V and 7-AAD positive Daudi cells after 24 h treatment with the indicated agents (top panels) and following 4 h co-culture with Vγ9Vδ2 T cells from one donor, at an E:T ratio of 5:1 (bottom panels)
Fig. 2
Fig. 2
Cytotoxic effects of Vγ9Vδ2 T cells combined with chemotherapy agents against solid tumour cell lines. Results indicate percentage cell death of tumour targets (means ± SEM; n = 3 donors) following 4 h co-culture with Vγ9Vδ2 T cells, measured in the MTS assay. Grey bars represent cytotoxicity of targets caused by Vγ9Vδ2 T cells only. Black bars represent cytotoxicity caused by Vγ9Vδ2 T cells following pre-treatment of targets with chemotherapy for 24 h (agent indicated in parentheses). White bars indicate controls of cell death caused by exposure of targets to chemotherapy for 24 h at the stated concentrations
Fig. 3
Fig. 3
Cytotoxic effects of Vγ9Vδ2 T cells combined with chemotherapy and zoledronate pre-treatment. a Results indicate percentage cell death of tumour targets (means ± SEM; n = 5 donors) following 4 h co-culture with Vγ9Vδ2 T cells at an E:T ratio of 5:1, measured in the MTS assay. Cytotoxicity of targets caused by Vγ9Vδ2 T cells alone are represented by grey bars and cytotoxicity as a result of zoledronate/Vγ9Vδ2 T cell combination is represented by black bars. Controls of cell death as a result of 24 h exposure of targets with zoledronate (50 μM) are indicated by white bars. b Cell death of DU-145 targets (means ± SEM; n = 5 donors) induced by indicated combinations of Vγ9Vδ2 T cells, zoledronate (50 μM) and etoposide (5 μM), at an E:T ratio of 5:1. White bars indicate cell death caused by 24 h exposure to agents alone. Black bars show cell death following 4 h Vγ9Vδ2 T cell co-culture. (Abbreviations: GDT Vγ9Vδ2 T cells; Zol Zoledronate, Etop Etoposide)
Fig. 4
Fig. 4
Patient Vγ9Vδ2 T cell cytotoxicity of solid tumour targets in combination with zoledronate. Cytotoxicity of tumour targets by patient Vγ9Vδ2 T cells after 4 h co-culture at a 5:1 E:T ratio (means ± SEM; n = 3; black bars), with or without pre-treatment with zoledronate at indicated concentrations. White bars show controls of cell death caused by zoledronate treatment alone
Fig. 5
Fig. 5
Cell line and Vγ9Vδ2 T cell phenotypes. a Representative overlay plots showing constitutive surface expression (filled histograms) of DR4, MICA/B and HLA-ABC on cell lines against appropriate isotype controls (hollow histograms). b Overlay plots representing surface (NKG2D, TRAIL, FasL) and intracellular (IFN-γ, perforin) expression on Vγ9Vδ2 T cells analysed at day 7 of in vitro culture. *IFN-γ production was assessed following non-specific stimulation with PMA and ionomycin
Fig. 6
Fig. 6
Mechanisms of Vγ9Vδ2 T cell recognition and cytotoxicity of pre-treated tumour targets. Results show cytotoxic inhibition (means ± SEM; n = 4 donors) of chemotherapy-pre-treated (a) and zoledronate-pre-treated (b) cell line targets using concanamycin A (CMA), mevastatin (Mev) and indicated blocking antibodies, following 4 h co-culture with Vγ9Vδ2 T cells at an E:T ratio of 5:1. Targets were pre-treated for 24 h prior to co-culture with Vγ9Vδ2 T cells
Fig. 7
Fig. 7
IFN-γ production and secretion by Vγ9Vδ2 T cells. a Histogram plots showing intracellular expression of IFN-γ in Vγ9Vδ2 T cells after non-specific stimulation with PMA and ionomycin or following 4 h co-culture with DU-145 targets that were pre-treated with the indicated agents. b ELISA results giving IFN-γ concentrations in culture supernatant, secreted by Vγ9Vδ2 T cells of healthy donors A and B following 4 h co-culture with different cell line targets that were pre-treated with the indicated sensitizing and blocking agents
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