A novel bifunctional anti-PD-L1/TGF-β Trap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells.
A novel bifunctional anti-PD-L1/TGF-β Trap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells.
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新型双功能抗PD-L1/TGF-β Trap融合蛋白（M7824）有效逆转人肺癌细胞的间充质化
DOI：
10.1080/2162402x.2017.1349589
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发表时间：
2017
期刊：
影响因子：
7.2
通讯作者：
Palena C
中科院分区：
文献类型：
--
作者：
David JM;Dominguez C;McCampbell KK;Gulley JL;Schlom J;Palena C
间充质化是上皮细胞逐渐丧失其良好分化的表型并采用间充质特征的细胞和分子程序。肿瘤间充质化发生在癌症进展为转移性疾病期间，并且还与对多种治疗剂的抗性相关，包括细胞毒性免疫细胞的杀伤。此外，肿瘤细胞可以通过上调检查点分子PD-L1来逃避免疫破坏，新兴研究发现间充质肿瘤中PD-L1表达更高。本文在非小细胞肺癌细胞（NSCLC）中研究了TGF-β1介导的间充质化与PD-L1之间的相关性。发现TGF-β1以Smad 2依赖性方式上调PD-L1基因转录，并且在NSCLC肿瘤中发现PD-L1与磷酸化Smad 2之间呈正相关。使用M7824（一种靶向PD-L1和TGF-β的新型临床阶段双功能药物）研究了单一药物靶向这2种负性免疫调节剂的潜力。在体外和体内用M7824处理NSCLC细胞可减弱TGF-β1介导的间充质化特征，包括间充质标志物表达、增殖抑制和化疗耐药性。这些结果表明，肿瘤细胞PD-L1的上调是NSCLC中TGF-β1诱导的免疫抑制的一种新机制，并且M7824治疗有可能同时阻断肿瘤间充质化和PD-L1依赖性免疫抑制。
Mesenchymalization is a cellular and molecular program in which epithelial cells progressively lose their well-differentiated phenotype and adopt mesenchymal characteristics. Tumor mesenchymalization occurs during the progression of cancer to metastatic disease, and is also associated with resistance to multiple therapeutics, including killing by cytotoxic immune cells. Furthermore, tumor cells can evade immune destruction by upregulating the checkpoint molecule PD-L1, and emerging research has found higher PD-L1 expression in mesenchymalized tumors. Here, the association between TGF-β1-mediated mesenchymalization and PD-L1 was investigated in non-small cell lung cancer cells (NSCLC). TGF-β1 was found to upregulate PD-L1 gene transcription in a Smad2-dependent manner, and a positive association between PD-L1 and phosphorylated Smad2 was found in NSCLC tumors. The potential to target these 2 negative immune regulators with a single agent was investigated using M7824, a novel clinical-stage bifunctional agent that targets both PD-L1 and TGF-β. Treatment of NSCLC cells with M7824 in vitro and in vivo attenuated features of TGF-β1-mediated mesenchymalization, including mesenchymal marker expression, proliferation suppression, and chemoresistance. These findings demonstrate that upregulation of tumor cell PD-L1 is a novel mechanism of TGF-β1-induced immunosuppression in NSCLC, and that treatment with M7824 has the potential to simultaneously block both tumor mesenchymalization and PD-L1-dependent immunosuppression.