EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression.
Animals
B7-H1 Antigen
/ genetics
Cell Line, Tumor
Disease Models, Animal
Drug Resistance, Neoplasm
/ genetics
ErbB Receptors
/ antagonists & inhibitors
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Lung Neoplasms
/ drug therapy
Mice
Molecular Targeted Therapy
Phosphatidylinositol 3-Kinases
/ metabolism
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins c-akt
/ metabolism
Signal Transduction
/ drug effects
T-Lymphocytes
/ immunology
Tumor Escape
/ genetics
Xenograft Model Antitumor Assays
EGFR-TKIs resistance
Immunotherapy
Lung cancer
PD-L1
Signaling pathways
Journal
Molecular cancer
ISSN: 1476-4598
Titre abrégé: Mol Cancer
Pays: England
ID NLM: 101147698
Informations de publication
Date de publication:
20 11 2019
20 11 2019
Historique:
received:
17
03
2019
accepted:
12
09
2019
entrez:
22
11
2019
pubmed:
22
11
2019
medline:
16
4
2020
Statut:
epublish
Résumé
The ATLANTIC trial reported that higher PD-L1 expression in tumors was involved in a higher objective response in patients with EGFR 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.
Sections du résumé
BACKGROUND
The ATLANTIC trial reported that higher PD-L1 expression in tumors was involved in a higher objective response in patients with EGFR
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.
Identifiants
pubmed: 31747941
doi: 10.1186/s12943-019-1073-4
pii: 10.1186/s12943-019-1073-4
pmc: PMC6864970
doi:
Substances chimiques
B7-H1 Antigen
0
CD274 protein, human
0
Protein Kinase Inhibitors
0
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
165Références
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