A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis.
A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis.
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DOI：
10.1371/journal.pone.0005061
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Dennis PA
中科院分区：
文献类型：
--
作者：
Granville CA;Memmott RM;Balogh A;Mariotti J;Kawabata S;Han W;Lopiccolo J;Foley J;Liewehr DJ;Steinberg SM;Fowler DH;Hollander MC;Dennis PA
K-Ras突变是人类肺腺癌的特征，几乎只发生在吸烟者身上。在临床前模型中，K-Ras突变是烟草致癌物驱动的肺肿瘤发生所必需的，并且足以在转基因小鼠中引起肺腺癌。由于这些突变赋予对常用的细胞毒性化疗和靶向药物的抗性，因此需要针对K-Ras的有效治疗。mTOR抑制剂如雷帕霉素可以阻止k - ras驱动的肺肿瘤发生，并改变细胞毒性和Foxp3+调节性T细胞的比例，提示肺相关T细胞可能在肿瘤发生中起重要作用。在三种依赖突变K-Ras的小鼠模型中研究了肺肿瘤的发生；烟草致癌物质驱动模型、同基因接种模型和转基因模型。用流式细胞术和免疫组织化学研究脾和肺相关T细胞。使用雷帕霉素、抗体或基因消融来消耗Foxp3+细胞。A/J小鼠在肿瘤发生前暴露于烟草致癌物质中，肺部相关Foxp3+细胞增加了两倍。在临床相关浓度下，雷帕霉素阻止了这种诱导，并使肺肿瘤减少了90%。在A/J小鼠中接种抗雷帕霉素的肺腺癌细胞，抗体介导的Foxp3+细胞缺失使肺肿瘤发生减少了80%。同样，缺乏Foxp3+细胞的K-Ras基因突变小鼠比Foxp3+细胞的小鼠患肺癌的几率低75%。Foxp3+调节性T细胞是k - ras介导的小鼠肺肿瘤发生所必需的。这些研究支持雷帕霉素或其他靶向Treg的药物在K-Ras驱动的人类肺癌中的临床试验。
K-Ras mutations are characteristic of human lung adenocarcinomas and occur almost exclusively in smokers. In preclinical models, K-Ras mutations are necessary for tobacco carcinogen-driven lung tumorigenesis and are sufficient to cause lung adenocarcinomas in transgenic mice. Because these mutations confer resistance to commonly used cytotoxic chemotherapies and targeted agents, effective therapies that target K-Ras are needed. Inhibitors of mTOR such as rapamycin can prevent K-Ras-driven lung tumorigenesis and alter the proportion of cytotoxic and Foxp3+ regulatory T cells, suggesting that lung-associated T cells might be important for tumorigenesis. Lung tumorigenesis was studied in three murine models that depend on mutant K-Ras; a tobacco carcinogen-driven model, a syngeneic inoculation model, and a transgenic model. Splenic and lung-associated T cells were studied using flow cytometry and immunohistochemistry. Foxp3+ cells were depleted using rapamycin, an antibody, or genetic ablation. Exposure of A/J mice to a tobacco carcinogen tripled lung-associated Foxp3+ cells prior to tumor development. At clinically relevant concentrations, rapamycin prevented this induction and reduced lung tumors by 90%. In A/J mice inoculated with lung adenocarcinoma cells resistant to rapamycin, antibody-mediated depletion of Foxp3+ cells reduced lung tumorigenesis by 80%. Likewise, mutant K-Ras transgenic mice lacking Foxp3+ cells developed 75% fewer lung tumors than littermates with Foxp3+ cells. Foxp3+ regulatory T cells are required for K-Ras-mediated lung tumorigenesis in mice. These studies support clinical testing of rapamycin or other agents that target Treg in K-Ras driven human lung cancer.
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