ATLANTIC试验报道,在EGFR+/ALK+非小细胞肺癌(NSCLC)患者中,较高的PD-L1表达与较高的客观反应有关。表明抗PD-1/PD-L1治疗作为晚期NSCLC的三线(或后期)治疗的可能性。因此,PD-L1在EGFR突变型NSCLC获得性EGFR-TKIs耐药前后的状态和调控机制的确定是有意义的。
PD-L1、c-MET、和HGF分析基于TCGA数据表和获得EGFR-TKI耐药前后的配对NSCLC标本。EGFR-TKI耐药NSCLC细胞具有三种众所周知的机制,c-MET扩增,肝细胞生长因子(HGF),和EGFR-T790M,检测PD-L1表达状态和免疫逃逸能力。使用PD-L1缺失的EGFR-TKIs敏感和耐药细胞评估小鼠异种移植模型中肿瘤的免疫逃逸能力。
PD-L1、c-MET、和HGF,基于TCGA数据表和配对NSCLC标本。此外,上述三种耐药机制在体内外增加了淋巴细胞的PD-L1表达,减弱了淋巴细胞的活化和细胞毒性,PD-L1的下调部分恢复了淋巴细胞的细胞毒性。MAPK和PI3K通路均参与三种耐药机制诱导的PD-L1过表达,而NF-κB通路仅参与T790M诱导的PD-L1表达。
HGF,MET扩增,EGFR-T790M通过不同的机制上调NSCLC中PD-L1的表达,促进肿瘤细胞的免疫逃逸。
The ATLANTIC trial reported that higher PD-L1 expression in tumors was involved in a higher objective response in patients with EGFR+/ALK+ non-small cell lung cancer (NSCLC), indicating the possibility of anti-PD-1/PD-L1 therapy as a third-line (or later) treatment for advanced NSCLC. Therefore, the determination of status and regulatory mechanisms of PD-L1 in EGFR mutant NSCLC before and after acquired EGFR-TKIs resistance are meaningful.
The correlation among PD-L1, c-MET, and HGF was analyzed based on TCGA datasheets and paired NSCLC specimens before and after acquired EGFR-TKI resistance. EGFR-TKI resistant NSCLC cells with three well-known mechanisms, c-MET amplification, hepatocyte growth factor (HGF), and EGFR-T790M, were investigated to determinate PD-L1 expression status and immune escape ability. PD-L1-deleted EGFR-TKIs sensitive and resistant cells were used to evaluate the immune escape ability of tumors in mice xenograft models.
Positive correlations were found among PD-L1, c-MET, and HGF, based on TCGA datasheets and paired NSCLC specimens. Moreover, the above three resistant mechanisms increased PD-L1 expression and attenuated activation and cytotoxicity of lymphocytes in vitro and in vivo, and downregulation of PD-L1 partially restored the cytotoxicity of lymphocytes. Both MAPK and PI3K pathways were involved in the three types of resistance mechanism-induced PD-L1 overexpression, whereas the NF-kappa B pathway was only involved in T790M-induced PD-L1 expression.
HGF, MET-amplification, and EGFR-T790M upregulate PD-L1 expression in NSCLC and promote the immune escape of tumor cells through different mechanisms.