TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts
TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts
复制标题
DOI：
10.1073/pnas.0705226104
复制
发表时间：
2007-07-24
影响因子：
11.1
通讯作者：
Tortora, Giampaolo
中科院分区：
文献类型：
--
作者：
Damiano, Vincenzo;Caputo, Rosa;Tortora, Giampaolo
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制仍不完全清楚。我们最近发现，TLR9 的合成激动剂免疫调节寡核苷酸 (IMO) 通过损害表皮生长因子受体 (EGFR) 信号传导发挥作用，并在 GEO 人类结肠癌异种移植物中与抗 EGFR 抗体西妥昔单抗有效协同，而在 VEGF 过表达西妥昔单抗耐药性 GEO 西妥昔单抗耐药 (GEO-CR) 肿瘤中无效。 VEGF 被 EGFR 激活，其过度表达导致对 EGFR 抑制剂产生耐药性。因此，我们使用IMO和抗VEGF抗体贝伐珠单抗作为工具来研究IMO对EGFR和血管生成的作用，并探索其在GEO、LS174T和GEO-CR癌症异种移植物中的治疗潜力。我们发现IMO增强了西妥昔单抗的抗体依赖性细胞介导的细胞毒性（ADCC）活性，而贝伐单抗没有ADCC，IMO无法增强它。尽管如此，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，随后抑制信号蛋白表达、微血管形成以及人类（而非小鼠）VEGF分泌。此外，IMO 抑制 VEGF 刺激的内皮细胞的生长、粘附、迁移和毛细血管形成。抗肿瘤活性与肿瘤细胞上 TLR9 的表达无关。这些研究表明，TLR9 的合成激动剂还通过影响内皮细胞功能的 EGFR 和 ADCC 独立机制干扰生长和血管生成，并为在结肠癌患者中将 IMO 与贝伐单抗和 EGFR 抑制药物联合使用提供了强有力的理由。
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. Intriguingly, their mechanisms of action on tumor growth and angiogenesis are still incompletely understood. We recently discovered that a synthetic agonist of TLR9, immune modulatory oligonucleoticle (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 bevacizurnab 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 anti body-dependent cell-mediated cytotoxicity (ADCC) activity of cetuximab, that bevacizurnab 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 bevacizurnab and EGFR inhibitory drugs in colon cancer patients.