Regulation of PD-L1 expression in non-small cell lung cancer by interleukin-1ß.

ABSTRACT

Introduction: Programmed 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-1ß (IL-1ß) plays a key role in regulation of PD-L1 expression in non-small cell lung cancer (NSCLC). Methods: We performed comprehensive screening of cytokine gene expression in NSCLC tissue using available single-cell RNA-Sequence data. Then we examined the role of IL-1ß in vitro to elucidate its induction of PD-L1 on NSCLC cells. Results: The IL-1ß gene is highly expressed in the tumor microenvironment, particularly in macrophages. The combination of IL-1ß and interferon-γ (IFN-γ) induced a synergistic increase in PD-L1 expression in NSCLC cell lines. IL-1ß 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-1ß and IFN-γ. Discussion: Our study reports high levels of IL-1ß 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-1ß-MAPK axis being a promising therapeutic target for attenuation of PD-L1-mediated suppression of antitumor immunity.