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

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

Automated summary

In this study, we found that PD-L1 expression in non-small cell lung cancer is regulated by IL-1 beta. The combination of IL-1 beta and IFN-gamma can synergistically increase PD-L1 expression and activate the MAPK signaling pathway. Inhibitors of MAPK signaling can block the upregulation of PD-L1 by IL-1 beta and IFN-gamma.