Cytotoxic effects of γδ T cells expanded ex vivo by a third generation bisphosphonate for cancer immunotherapy
Cytotoxic effects of γδ T cells expanded ex vivo by a third generation bisphosphonate for cancer immunotherapy
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DOI：
10.1002/ijc.20987
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发表时间：
2005-08
影响因子：
6.4
通讯作者：
Kiyoshi Sato;S. Kimura;H. Segawa;A. Yokota;S. Matsumoto;J. Kuroda;M. Nogawa;T. Yuasa;Y. Kiyono;H. Wada;T. Maekawa
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文献类型：
--
作者：
Kiyoshi Sato;S. Kimura;H. Segawa;A. Yokota;S. Matsumoto;J. Kuroda;M. Nogawa;T. Yuasa;Y. Kiyono;H. Wada;T. Maekawa
含氮双膦酸盐(N-BPS)广泛用于治疗骨科疾病，通过使RAS蛋白失活而具有直接的抗肿瘤作用。除了直接的抗肿瘤活性外，N-BPS还能扩增gdγδT细胞，表现出主要的组织相容性复合体--不受限制的裂解活性。BPS在靶细胞中积累中间代谢物，可能是肿瘤抗原。本研究的目的是阐明最强的N-BP，唑来膦酸盐对体外扩增的gdγδT细胞的细胞毒作用。我们特别强调了ZOL对靶细胞的预处理的重要性；1MμM ZOL+IL-2使14天的gdγδT细胞绝对数增加298-768倍。小细胞肺癌和纤维肉瘤细胞株经5Mμ-M-ZOL处理后，对gd-γδT细胞裂解的敏感性明显增加。而未经处理的细胞系对GDT细胞裂解的敏感性要低得多。视频显微镜清楚地显示，经ZOL处理后的gdγδT细胞在3小时内即可杀死靶细胞。预先给予80Mμg/kgZOL也能显著增强gdγδT细胞对移植瘤小鼠的抗肿瘤活性。这些结果表明，ZOL能显著刺激gdγδT细胞的增殖，且gdγδT细胞需要用zol预先处理才能产生杀伤靶细胞的活性。©2005 Wiley-Liss Inc.
Nitrogen containing‐bisphosphonates (N‐BPs), widely used to treat bone diseases, have direct antitumor effects via the inactivation of Ras proteins. In addition to the direct antitumor activities, N‐BPs expand gdγδT cells, which exhibit major histocompatibility complex‐unrestricted lytic activity. BPs accumulate intermediate metabolites which may be tumor antigens in target cells. The purpose of our study was to clarify the cytotoxicity of gdγδ T cells expanded ex vivo by the most potent N‐BP, zoledronate (ZOL). Especially, we focused on the importance of pretreatment against target cells also with ZOL; 1 mμM ZOL plus IL‐2 increased the absolute number of gdγδT cells 298–768 fold for 14 days incubation. The small cell lung cancer and fibrosarcoma cell lines pretreated with 5 mμM ZOL showed a marked increase in sensitivity to lysis by gdγδT cells. While, untreated cell lines were much less sensitive to lysis by gdT cells. Video microscopy clearly demonstrated that gdγδT cells killed target cells pre‐treated with ZOL within 3 hr. Pretreatment with 80 mμg/kg ZOL also significantly enhanced the antitumor activity of gdγδT cells in mice xenografted with SBC‐5 cells. These findings show that ZOL significantly stimulated the proliferation of gdγδT cells and that gdγδT cells required pre‐treatment with ZOL for cytotoxic activity against target cells. © 2005 Wiley‐Liss, Inc.