EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression

Molecular Cancer

Ke Li¹  Xiaojuan Zhang²  Wei Wang²  Rong Wang²  Shunli Peng²  Longhui Zhong²  Yueyun Ma²  Sachiko Arai³  Seiji Yano³  Akihiro Nishiyama³ 

[1] Center for Clinical Medicine Research, Nanfang Hospital, Southern Medical University;Department of Radiation Oncology, Nanfang Hospital, Southern Medical University;Divisions of Medical Oncology, Cancer Research Institute, Kanazawa University;

关键词: PD-L1;    EGFR-TKIs resistance;    Signaling pathways;    Lung cancer;    Immunotherapy;   

DOI  :  10.1186/s12943-019-1073-4

来源: DOAJ

【 摘 要 】

Abstract Background 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. Methods 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. Results 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. Conclusions HGF, MET-amplification, and EGFR-T790M upregulate PD-L1 expression in NSCLC and promote the immune escape of tumor cells through different mechanisms.

【 授权许可】

Unknown