Regulation of PD-L1 expression in K-ras-driven cancers through ROS-mediated FGFR1 signaling

Christophe Glorieux, Xiaojun Xia, Yong Qiao He, Yumin Hu, Kelly Cremer, Annie Robert, Junchen Liu, Fen Wang, Jianhua Ling, Paul J. Chiao, Peng Huang

Research output: Contribution to journalArticle

Abstract

K-ras mutations are major genetic events that drive cancer development associated with aggressive malignant phenotypes, while expression of the immune checkpoint molecule PD-L1 plays a key role in cancer evasion of the immune surveillance that also profoundly affects the patient outcome. However, the relationship between K-ras oncogenic signal and PD-L1 expressions as an important area that requires further investigation. Using both in vitro and in vivo experimental models of K-ras-driven cancer, we found that oncogenic K-ras significantly enhanced PD-L1 expression through a redox-mediated mechanism. Activation of K-rasG12V promoted ROS generation and induced FGFR1 expression, leading to a significant upregulation of PD-L1. We further showed that exogenous ROS such as hydrogen peroxide alone was sufficient to activate FGFR1 and induce PD-L1, while antioxidants could largely abrogate PD-L1 expression in K-ras mutant cells, indicating a critical role of redox regulation. Importantly, genetic knockout of FGFR1 led to a decrease in PD-L1 expression, and impaired tumor growth in vivo due to a significant increase of T cell infiltration in the tumor tissues and thus enhanced T-cell-mediated tumor suppression. Our study has identified a novel mechanism by which K-ras promotes PD-L1 expression, and suggests that modulation of ROS or inhibition of the FGFR1 pathway could be a novel strategy to abrogate PD-L1-mediated immunosuppression and thus potentially improve the efficacy of immunotherapy in K-ras-driven cancers.

Original languageEnglish (US)
Article number101780
JournalRedox Biology
Volume38
DOIs
StatePublished - Jan 2021

Keywords

  • FGFR1
  • K-ras
  • PD-L1
  • ROS

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

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