Frontiers in Immunology (Jun 2023)

Regulation of PD-L1 expression in non–small cell lung cancer by interleukin-1β

  • Aiko Hirayama,
  • Kentaro Tanaka,
  • Hirono Tsutsumi,
  • Takayuki Nakanishi,
  • Sho Yamashita,
  • Shun Mizusaki,
  • Yumiko Ishii,
  • Keiichi Ota,
  • Yasuto Yoneshima,
  • Eiji Iwama,
  • Isamu Okamoto

DOI
https://doi.org/10.3389/fimmu.2023.1192861
Journal volume & issue
Vol. 14

Abstract

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IntroductionProgrammed cell death–ligand 1 (PD-L1) is a biomarker for prediction of the clinical efficacy of immune checkpoint inhibitors in various cancer types. The role of cytokines in regulation of PD-L1 expression in tumor cells has not been fully characterized, however. Here we show that interleukin-1β (IL-1β) plays a key role in regulation of PD-L1 expression in non–small cell lung cancer (NSCLC).MethodsWe performed comprehensive screening of cytokine gene expression in NSCLC tissue using available single-cell RNA-Sequence data. Then we examined the role of IL-1β in vitro to elucidate its induction of PD-L1 on NSCLC cells.ResultsThe IL-1β gene is highly expressed in the tumor microenvironment, particularly in macrophages. The combination of IL-1β and interferon-γ (IFN-γ) induced a synergistic increase in PD-L1 expression in NSCLC cell lines. IL-1β and IFN-γ also cooperatively activated mitogen-activated protein kinase (MAPK) signaling and promoted the binding of downstream transcription factors to the PD-L1 gene promoter. Furthermore, inhibitors of MAPK signaling blocked upregulation of PD-L1 by IL-1β and IFN-γ.DiscussionOur study reports high levels of IL-1β in the tumor microenvironment may cooperate with IFN-γ to induce maximal PD-L1 expression in tumor cells via activation of MAPK signaling, with the IL-1β–MAPK axis being a promising therapeutic target for attenuation of PD-L1–mediated suppression of antitumor immunity.

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