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 |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:18 |
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| Enthalten in: |
Molecular cancer - 18(2019), 1 vom: 20. Nov., Seite 165 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Peng, Shunli [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.04.2020 Date Revised 15.04.2020 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1186/s12943-019-1073-4 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM303507675 |
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| 245 | 1 | 0 | |a EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression |
| 264 | 1 | |c 2019 | |
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| 500 | |a Date Completed 15.04.2020 | ||
| 500 | |a Date Revised 15.04.2020 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a CONCLUSIONS: HGF, MET-amplification, and EGFR-T790M upregulate PD-L1 expression in NSCLC and promote the immune escape of tumor cells through different mechanisms | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a EGFR-TKIs resistance | |
| 650 | 4 | |a Immunotherapy | |
| 650 | 4 | |a Lung cancer | |
| 650 | 4 | |a PD-L1 | |
| 650 | 4 | |a Signaling pathways | |
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| 700 | 1 | |a Wang, Rong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiaojuan |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Yueyun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhong, Longhui |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Ke |e verfasserin |4 aut | |
| 700 | 1 | |a Nishiyama, Akihiro |e verfasserin |4 aut | |
| 700 | 1 | |a Arai, Sachiko |e verfasserin |4 aut | |
| 700 | 1 | |a Yano, Seiji |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Wei |e verfasserin |4 aut | |
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