High Phosphoantigen Levels in Bisphosphonate-Treated Human Breast Tumors Promote Vγ9Vδ2 T-Cell Chemotaxis and Cytotoxicity In Vivo
High Phosphoantigen Levels in Bisphosphonate-Treated Human Breast Tumors Promote Vγ9Vδ2 T-Cell Chemotaxis and Cytotoxicity In Vivo
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DOI：
10.1158/0008-5472.can-10-3862
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发表时间：
2011-07-01
期刊：
影响因子：
11.2
通讯作者：
Clezardin, Philippe
中科院分区：
文献类型：
--
作者：
Benzaid, Ismahene;Moenkkoenen, Hannu;Clezardin, Philippe
含氮二膦酸唑来膦酸（ZOL）是一种有效的法尼酯焦磷酸合成酶抑制剂，阻断甲戊酸途径，导致细胞内积累异戊烯基焦磷酸/三磷酸i -腺苷-5′-基酯3-（3-甲基-3-烯基）酯（IPP/ApppI）甲戊酸代谢产物。zol处理的癌细胞中IPP/ApppI的积累可能被V γ 9V δ 2 T细胞识别为肿瘤磷酸化抗原。然而，这些发现在体内的意义在很大程度上仍然未知。在本研究中，我们研究了zol处理的乳腺癌细胞中V γ 9V δ 2 T细胞的抗癌活性与细胞内IPP/ApppI水平的相关性。我们发现zol治疗后不同人乳腺癌细胞系IPP/ appi的产生有显著差异。与纯化的人V γ 9V δ 2 T细胞共培养，导致IPP/ appi依赖性几乎完全杀死zol处理的乳腺癌细胞。在zol处理的小鼠皮下乳腺癌异种移植物中，V γ 9V δ 2 T细胞浸润并抑制IPP/ApppI水平高的肿瘤的生长，而不抑制IPP/ApppI水平低的肿瘤的生长。此外，IPP/ApppI不仅在癌细胞中积累，而且还能分泌，促进V γ 9V δ 2 t细胞对肿瘤的趋化性。如果没有V γ 9V δ 2 t细胞扩增，ZOL对肿瘤生长没有抑制作用。这些发现表明，ZOL治疗后产生高IPP/ApppI水平的癌症最有可能受益于V γ 9V δ 2 t细胞介导的免疫治疗。癌症Res;71 (13);4562 - 72。(c) 2011年aacr。
The nitrogen-containing bisphosphonate zoledronic acid (ZOL), a potent inhibitor of farnesyl pyrophosphate synthase, blocks the mevalonate pathway, leading to intracellular accumulation of isopentenyl pyrophosphate/triphosphoric acid I-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester (IPP/ApppI) mevalonate metabolites. IPP/ApppI accumulation in ZOL-treated cancer cells may be recognized by V gamma 9V delta 2 T cells as tumor phosphoantigens in vitro. However, the significance of these findings in vivo remains largely unknown. In this study, we investigated the correlation between the anticancer activities of V gamma 9V delta 2 T cells and the intracellular IPP/ApppI levels in ZOL-treated breast cancer cells in vitro and in vivo. We found marked differences in IPP/ApppI production among different human breast cancer cell lines post-ZOL treatment. Coculture with purified human V gamma 9V delta 2 T cells led to IPP/ApppI-dependent near-complete killing of ZOL-treated breast cancer cells. In ZOL-treated mice bearing subcutaneous breast cancer xenografts, V gamma 9V delta 2 T cells infiltrated and inhibited growth of tumors that produced high IPP/ApppI levels, but not those expressing low IPP/ApppI levels. Moreover, IPP/ApppI not only accumulated in cancer cells but it was also secreted, promoting V gamma 9V delta 2 T-cell chemotaxis to the tumor. Without V gamma 9V delta 2 T-cell expansion, ZOL did not inhibit tumor growth. These findings suggest that cancers-producing high IPP/ApppI levels after ZOL treatment are most likely to benefit from V gamma 9V delta 2 T-cell-mediated immunotherapy. Cancer Res; 71(13); 4562-72. (C) 2011 AACR.