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Epidermal growth factor induces STAT1 expression to exacerbate the IFNr-mediated PD-L1 axis in epidermal growth factor receptor-positive cancers
- Source :
- Molecular carcinogenesis. 57(11)
- Publication Year :
- 2018
-
Abstract
- The epidermal growth factor (EGF) receptor (EGFR) overexpressed in many cancers, including lung and head and neck cancers, and is involved in cancer cell progression and survival. PD-L1, increases in tumor cells to evade and inhibit CD8+ T cells, is a clinical immunotherapeutic target. This study investigated the molecular mechanism of EGF on regulating PD-L1 in EGFR-positive cancers and determined potential agents to reduce PD-L1 expression. RNA sequencing (RNAseq) and bioinformatics analysis were performed to determine potential driver genes that regulate PD-L1 in tumor cells-derived tumorspheres which mimicking cancer stem cells. Then, the specific inhibitors targeting EGFR were applied to reduce the expression of PD-L1 in vitro and in vivo. We validated that EGF could induce PD-L1 expression in the selected EGFR-positive cancers. RNAseq results revealed that STAT1 increased as a driver gene in KOSC-3-derived tumorspheres; these data were analyzed using PANTHER followed by NetworkAnalyst. The blockade of EGFR by afatinib resulted in decreased STAT1 and IRF-1 levels, both are transcriptional factors of PD-L1, and disabled the IFNr-STAT1-mediated PD-L1 axis in vitro and in vivo. Moreover, STAT1 knockdown significantly reduced EGF-mediated PD-L1 expression, and ruxolitinib, a JAK1/JAK2 inhibitor, significantly inhibited STAT1 phosphorylation to reduce the IFNr-mediated PD-L1 axis. These results indicate that EGF exacerbates PD-L1 by increasing the protein levels of STAT1 to enforce the IFNr-JAK1/2-mediated signaling axis in selected EGFR-positive cancers. The inhibition of EGFR by afatinib significantly reduced PD-L1 and may be a potential strategy for enhancing immunotherapeutic efficacy.
- Subjects :
- 0301 basic medicine
Male
Cancer Research
Afatinib
B7-H1 Antigen
Immunophenotyping
03 medical and health sciences
Interferon-gamma
Mice
0302 clinical medicine
Cancer stem cell
Epidermal growth factor
Cell Line, Tumor
Neoplasms
medicine
Animals
Humans
Epidermal growth factor receptor
Lung cancer
Molecular Biology
Protein Kinase Inhibitors
Gene knockdown
biology
Epidermal Growth Factor
medicine.disease
ErbB Receptors
Gene Expression Regulation, Neoplastic
030104 developmental biology
STAT1 Transcription Factor
030220 oncology & carcinogenesis
Cancer cell
Cancer research
biology.protein
CD8
Biomarkers
medicine.drug
Subjects
Details
- ISSN :
- 10982744
- Volume :
- 57
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Molecular carcinogenesis
- Accession number :
- edsair.doi.dedup.....369b1c7db3404f48d7a08003104d5f2f