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

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..

Medienart:

E-Artikel

Erscheinungsjahr:

2019

Erschienen:

2019

Enthalten in:

Zur Gesamtaufnahme - volume:18

Enthalten in:

Molecular cancer - 18(2019), 1 vom: 20. Nov.

Sprache:

Englisch

Beteiligte Personen:

Peng, Shunli [VerfasserIn]
Wang, Rong [VerfasserIn]
Zhang, Xiaojuan [VerfasserIn]
Ma, Yueyun [VerfasserIn]
Zhong, Longhui [VerfasserIn]
Li, Ke [VerfasserIn]
Nishiyama, Akihiro [VerfasserIn]
Arai, Sachiko [VerfasserIn]
Yano, Seiji [VerfasserIn]
Wang, Wei [VerfasserIn]

Links:

Volltext [kostenfrei]

Themen:

EGFR-TKIs resistance
Immunotherapy
Lung cancer
PD-L1
Signaling pathways

Anmerkungen:

© The Author(s). 2019

doi:

10.1186/s12943-019-1073-4

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

SPR029101239