EGFR-targeted therapy alters the tumor microenvironment in EGFR-driven lung tumors: Implications for combination therapies
EGFR-targeted therapy alters the tumor microenvironment in EGFR-driven lung tumors: Implications for combination therapies
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EGFR 靶向治疗改变 EGFR 驱动的肺部肿瘤的肿瘤微环境：联合治疗的意义
DOI：
10.1002/ijc.32191
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发表时间：
2019-09-01
影响因子：
6.4
通讯作者：
Zhou, Caicun
中科院分区：
文献类型：
--
作者：
Jia, Yijun;Li, Xuefei;Zhou, Caicun
靶向程序性细胞死亡受体/配体1（PD-1/PD-L1）通路的免疫检查点抑制剂极大地改善了非小细胞肺癌（NSCLC）的临床管理。尽管如此，PD-1/PD-L1抑制剂单药治疗EGFR突变患者的优效性已被证明是中等的。对免疫检查点抑制剂的不良反应的一种提出的机制是免疫抑制性肿瘤微环境。因此，我们利用两种本地EGFR驱动的肺肿瘤模型来研究对EGFR-TKI治疗的动态微环境反应。我们观察到，在早期阶段，敏感的EGFR-TKI引起明显的肿瘤缩小，伴随着细胞毒性CD 8（+）T细胞和树突状细胞的增加，Foxp 3（+）T细胞的根除，以及巨噬细胞M2样极化的抑制。然而，可能对免疫介导的抗癌方法联合治疗最有益的肿瘤微环境变化只是暂时的，并随着治疗的继续而消失。同时，髓源性抑制细胞（MDSC），特别是单核MDSC的水平在整个治疗过程中持续升高。血清中炎症因子的分析表明，EGFR-TKI增加了IL-10和CCL-2的水平。我们的研究系统地分析了EGFR-TKI体内肿瘤微环境的动态变化。这些结果对使用EGFR-TKI的联合治疗具有意义。在设计临床试验时，需要考虑治疗的最佳顺序和将肿瘤微环境调节到可能有利于抗肿瘤免疫应答的状态的策略。
Immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD-1/PD-L1) pathway have profoundly improved the clinical management of non-small-cell lung cancer (NSCLC). Nevertheless, the superiority of single-agent PD-1/PD-L1 inhibitors in pretreated EGFR mutant patients has turned out to be moderate. One proposed mechanism for poor response to immune checkpoint inhibitors is an immunosuppressive tumor microenvironment. Therefore, we utilized two autochthonous EGFR-driven lung tumor models to investigate dynamic microenvironmental responses to EGFR-TKI treatment. We observed that at an early stage, sensitive EGFR-TKIs caused obvious tumor shrinkage accompanied by increased cytotoxic CD8(+) T cells and dendritic cells, eradication of Foxp3(+) Tregs, and inhibition of M2-like polarization of macrophages. However, the tumor microenvironmental changes that may be most beneficial for combination treatment with immune-mediated anticancer approaches were only temporary and disappeared as treatment continued. Meanwhile, the level of myeloid-derived suppressor cells (MDSCs), particularly mononuclear MDSCs, was consistently elevated throughout the treatment. Analysis of inflammatory factors in serum showed that EGFR-TKIs increased the levels of IL-10 and CCL-2. Our study systematically analyzed dynamic changes in tumor microenvironments responding to EGFR-TKIs in vivo. The results have implications for combination therapy using EGFR-TKIs. The optimal sequence of the treatment and strategies that modulate the tumor microenvironment to a state that may favor antitumor immune responses need to be considered when designing clinical trials.