Chemotherapy and zoledronate sensitize solid tumour cells to Vγ9Vδ2 T cell cytotoxicity
Chemotherapy and zoledronate sensitize solid tumour cells to Vγ9Vδ2 T cell cytotoxicity
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DOI：
10.1007/s00262-007-0279-2
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发表时间：
2007-08-01
影响因子：
5.8
通讯作者：
Nicol, Andrew J.
中科院分区：
文献类型：
--
作者：
Mattarollo, Stephen R.;Kenna, Tony;Nicol, Andrew J.
基于细胞免疫的疗法与化疗和其他抗肿瘤药物的组合可能在许多形式的癌症的治疗中具有显著的临床益处。γ δ（γ δ）T细胞由于其有效的抗肿瘤细胞毒性和相对容易在体外产生而特别感兴趣用于这种联合疗法。在这里，我们证明了高水平的细胞毒性对实体瘤衍生的细胞系与联合治疗，利用V γ 9V δ 2 T细胞，化疗药物和双膦酸盐，唑来膦酸盐。用低浓度的化疗剂或唑来膦酸盐预处理使肿瘤细胞对V γ 9V δ 2 T细胞的快速杀伤敏感，细胞毒性水平接近90%。此外，唑来膦酸盐增强了化疗诱导的肿瘤细胞对V γ 9V δ 2 T细胞毒性的敏感性，在某些情况下导致肿瘤靶点几乎100%溶解。在TCR依赖性和类异戊二烯介导的肿瘤细胞识别后，V γ 9V δ 2 T细胞的细胞毒性由穿孔素介导。在暴露于致敏靶标后，还诱导V γ 9V δ 2 T细胞产生IFN-γ。我们的结论是，在化疗和唑来膦酸盐治疗后，在适当的时间间隔给予V γ 9V δ 2 T细胞，可以大大增加一系列恶性肿瘤的抗肿瘤活性。
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. Gamma delta (gamma delta) 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 V gamma 9V delta 2 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 V gamma 9V delta 2 T cells with levels of cytotoxicity approaching 90%. In addition, zoledronate enhanced the chemotherapy-induced sensitization of tumour cells to V gamma 9V delta 2 T cell cytotoxicity resulting in almost 100% lysis of tumour targets in some cases. V gamma 9V delta 2 T cell cytotoxicity was mediated by perforin following TCR-dependent and isoprenoid-mediated recognition of tumour cells. Production of IFN-gamma by V gamma 9V delta 2 T cells was also induced after exposure to sensitized targets. We conclude that administration of V gamma 9V delta 2 T cells at suitable intervals after chemotherapy and zoledronate may substantially increase antitumour activities in a range of malignancies.