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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts
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TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts

机译：TLR9激动剂通过与贝伐单抗协同作用的敏感性和西妥昔单抗耐药结肠癌异种移植物的不同机制起作用。

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Synthetic agonists of Toll-like receptor 9 (TLR9), a class of agents that induce specific immune response, exhibit antitumor activity and are currently being investigated in cancer patients. Intrigu-ingly, their mechanisms of action on tumor growth and angiogen-esis are still incompletely understood. We recently discovered that a synthetic agonist of TLR9, immune modulatory oligonucleotide (IMO), acts by impairing epidermal growth factor receptor (EGFR) signaling and potently synergizes with anti-EGFR antibody cetuximab in GEO human colon cancer xenografts, whereas it is ineffective in VEGF-overexpressing cetuximab-resistant GEO cetuximab-resistant (GEO-CR) tumors. VEGF is activated by EGFR, and its overexpression causes resistance to EGFR inhibitors. Therefore, we used IMO and the anti-VEGF antibody bevacizumab as tools to study IMO's role on EGFR and angiogenesis and to explore its therapeutic potential in GEO, LS174T, and GEO-CR cancer xenografts. We found that IMO enhances the antibody-dependent cell-mediated cytotoxicity (ADCC) activity of cetuximab, that bevacizumab has no ADCC, and IMO is unable to enhance it. Nevertheless, the IMO-plus-bevacizumab combination synergistically inhibits the growth of GEO and LS174T as well as of GEO-CR tumors, preceded by inhibition of signaling protein expression, microvessel formation, and human, but not murine, VEGF secretion. Moreover, IMO inhibited the growth, adhesion, migration, and capillary formation of VEGF-stimulated endothelial cells. The antitumor activity was irrespective of the TLR9 expression on tumor cells. These studies demonstrate that synthetic agonists of TLR9 interfere with growth and angiogenesis also by EGFR- and ADCC-independent mechanisms affecting endothelial cell functions and provide a strong rationale to combine IMO with bevacizumab and EGFR inhibitory drugs in colon cancer patients.
机译：Toll样受体9（TLR9）的合成激动剂是一类诱导特异性免疫反应的药物，具有抗肿瘤活性，目前正在癌症患者中进行研究。有趣的是，它们对肿瘤生长和血管生成的作用机理仍未完全了解。我们最近发现，TLR9的合成激动剂，免疫调节性寡核苷酸（IMO），可通过破坏表皮生长因子受体（EGFR）信号传导而发挥作用，并与GEO结肠癌异种移植物中的抗EGFR抗体西妥昔单抗有效协同作用，而对VEGF无效过表达西妥昔单抗耐药的GEO耐西妥昔单抗（GEO-CR）的肿瘤。 VEGF被EGFR激活，其过表达引起对EGFR抑制剂的抗性。因此，我们使用IMO和抗VEGF抗体贝伐单抗作为工具来研究IMO在EGFR和血管生成中的作用，并探讨其在GEO，LS174T和GEO-CR癌症异种移植物中的治疗潜力。我们发现，IMO增强西妥昔单抗的抗体依赖性细胞介导的细胞毒性（ADCC）活性，贝伐单抗没有ADCC，而IMO无法增强它。但是，IMO加贝伐单抗组合可协同抑制GEO和LS174T以及GEO-CR肿瘤的生长，然后抑制信号蛋白的表达，微血管的形成以及人类而非鼠类VEGF的分泌。此外，IMO抑制了VEGF刺激的内皮细胞的生长，粘附，迁移和毛细血管形成。该抗肿瘤活性与肿瘤细胞上的TLR9表达无关。这些研究表明，TLR9的合成激动剂还通过不依赖于EGFR和ADCC的机制影响内皮细胞功能来干扰生长和血管生成，并为将IMO与贝伐单抗和EGFR抑制药物联合用于结肠癌患者提供了强有力的理由。

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