Down-regulation of human complement factor h sensitizes non-small cell lung cancer cells to complement attack and reduces in vivo tumor growth
Down-regulation of human complement factor h sensitizes non-small cell lung cancer cells to complement attack and reduces in vivo tumor growth
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DOI：
10.4049/jimmunol.178.9.5991
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发表时间：
2007-05-01
影响因子：
4.4
通讯作者：
Pio, Ruben
中科院分区：
文献类型：
--
作者：
Ajona, Daniel;Hsu, Yi-Fan;Pio, Ruben
恶性细胞通常通过增强补体抑制剂的表达而对补体活化具有抗性。在这项工作中，我们研究了两个非小细胞肺癌细胞系，H1264和A549，在经典的补体途径激活后，H因子，CD46，CD55和CD59的保护作用。用针对每个细胞系产生的多克隆Ab激活补体。在用中和Ab阻断因子H活性后，C3沉积和C5a释放更有效。此外，因子H和CD59的组合抑制显著增加补体介导的溶解。CD46和CD55在补体激活的控制中没有显示出任何效果。使用小干扰RNA敲低A549细胞上的因子H表达。在体内生长的H因子缺陷细胞在无胸腺小鼠显着减少。C3免疫细胞化学显示这些细胞中补体的活化增强。此外，当用眼镜蛇毒因子耗尽小鼠的补体时，生长恢复，进一步证明补体在体内生长减少中是重要的。总之，我们发现肺癌细胞表达补体抑制因子H可以阻止补体激活并改善体内肿瘤的发展。这可能对补体介导的免疫疗法的效率产生重要影响。
Malignant cells are often resistant to complement activation through the enhanced expression of complement inhibitors. In this work, we examined the protective role of factor H, CD46, CD55, and CD59 in two non-small cell lung cancer cell lines, H1264 and A549, upon activation of the classical pathway of complement. Complement was activated with polyclonal Abs raised against each cell line. After blocking factor H activity with a neutralizing Ab, C3 deposition and C5a release were more efficient. Besides, a combined inhibition of factor H and CD59 significantly increased complement-mediated lysis. CD46 and CD55 did not show any effect in the control of complement activation. Factor H expression was knockdown on A549 cells using small interfering RNA. In vivo growth of factor H-deficient cells in athymic mice was significantly reduced. C3 immunocytochemistry on explanted xenografts showed an enhanced activation of complement in these cells. Besides, when mice were depleted of complement with cobra venom factor, growth was recovered, providing further evidence that complement was important in the reduction of in vivo growth. In conclusion, we show that expression of the complement inhibitor factor H by lung cancer cells can prevent complement activation and improve tumor development in vivo. This may have important consequences in the efficiency of complement-mediated immunotherapies.