Accelerated tumor growth mediated by sublytic levels of antibody-induced complement activation is associated with activation of the PI3K/AKT survival pathway.
Accelerated tumor growth mediated by sublytic levels of antibody-induced complement activation is associated with activation of the PI3K/AKT survival pathway.
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DOI：
10.1158/1078-0432.ccr-13-0088
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发表时间：
2013-09-01
期刊：
影响因子：
--
通讯作者：
Livingston PO
中科院分区：
文献类型：
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作者：
Wu X;Ragupathi G;Panageas K;Hong F;Livingston PO
我们提出了低水平的肿瘤细胞结合抗体靶向神经节苷脂可能加速肿瘤生长的可能性。为了检验这一假设，我们在用表达GM 2、GD 2、GD 3和CD 20的肿瘤攻击后，用一系列针对这些抗原的mAb剂量处理小鼠，并在体外测试相同mAb的活性。我们还探讨了补体介导的肿瘤生长加速背后的机制，我们观察到和一种方法来克服it. Serologically可检测水平的抗GM 2的IgM-单克隆抗体能够延迟或阻止肿瘤生长的高GM 2表达细胞系在体外和在一个SCID小鼠模型，而非常低的水平，这种mAb导致轻微的，但一致的加速肿瘤生长在这两种设置。令人惊讶的是，这不限于靶向GM 2的IgM抗体，而是与靶向GD 3的IgG-mAb一致。这些发现通过使用针对这些抗原以及GD 2和CD 20（使用Rituxan）的抗体进行的体外研究得到了反映，并且在所有情况下都显示出补体依赖性。低mAb水平引发的补体介导的培养肿瘤细胞系加速生长与PI 3 K/AKT生存途径的激活以及p-AKT和p-PRAS 40水平的显着升高相关。这种补体介导的PI 3 K激活和体外和体内加速的肿瘤生长被PI 3 K抑制剂NVP-BEZ 235和渥曼青霉素消除。这些PI 3 K抑制剂还显著增加了高剂量这4种mAb的功效。我们的研究结果表明，PI 3 K/AKT通路及其信号网络的操纵可以显着增加被动给药的单克隆抗体和疫苗诱导的抗体靶向各种肿瘤细胞表面抗原的效力。
We addressed the possibility that low levels of tumor cell bound antibodies targeting gangliosides might accelerate tumor growth. To test this hypothesis, we treated mice with a range of mAb doses against GM2, GD2, GD3 and CD20 after challenge with tumors expressing these antigens and tested the activity of the same mAbs in-vitro. We also explored the mechanisms behind the complement-mediated tumor growth acceleration that we observed and an approach to overcome it. Serologically detectable levels of IgM-mAb against GM2 are able to delay or prevent tumor growth of high GM2-expressing cell lines both in-vitro and in a SCID mouse model, while very low levels of this mAb resulted in slight but consistent acceleration of tumor growth in both settings. Surprisingly, this is not restricted to IgM antibodies targeting GM2 but consistent against IgG-mAb targeting GD3 as well. These findings were mirrored by in-vitro studies with antibodies against these antigens as well as GD2 and CD20 (with Rituxan), and shown to be complement-dependent in all cases. Complement-mediated accelerated growth of cultured tumor cell lines initiated by low mAb levels was associated with activation of the PI3K/AKT survival pathway and significantly elevated levels of both p-AKT and p-PRAS40. This complement-mediated PI3K-activation and accelerated tumor growth in-vitro and in-vivo are eliminated by PI3K-inhibitors NVP-BEZ235 and Wortmannin. These PI3K-inhibitors also significantly increased efficacy of high doses of these 4 mAbs. Our findings suggest that manipulation of the PI3K/AKT pathway and its signaling network can significantly increase the potency of passively administered mAbs and vaccine-induced-antibodies targeting a variety of tumor-cell-surface-antigens.