Epidermal growth factor induces STAT1 expression to exacerbate the IFNr-mediated PD-L1 axis in epidermal growth factor receptor-positive cancers

Chun Chia Cheng, Hsin Chi Lin, Kaun Jer Tsai, Ya Wen Chiang, Ken Hong Lim, Caleb Gon Shen Chen, Ying Wen Su, Cheng Liang Peng, Ai Sheng Ho, Ling Huang, Yu Cheng Chang, Huan Chau Lin, Jungshan Chang, Yi Fang Chang

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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.

Original languageEnglish
Pages (from-to)1588-1598
Number of pages11
JournalMolecular Carcinogenesis
Volume57
Issue number11
DOIs
Publication statusPublished - Nov 1 2018

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Keywords

  • afatinib
  • EGFR
  • lung cancer
  • PD-L1
  • STAT1

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Cheng, C. C., Lin, H. C., Tsai, K. J., Chiang, Y. W., Lim, K. H., Chen, C. G. S., Su, Y. W., Peng, C. L., Ho, A. S., Huang, L., Chang, Y. C., Lin, H. C., Chang, J., & Chang, Y. F. (2018). Epidermal growth factor induces STAT1 expression to exacerbate the IFNr-mediated PD-L1 axis in epidermal growth factor receptor-positive cancers. Molecular Carcinogenesis, 57(11), 1588-1598. https://doi.org/10.1002/mc.22881