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

Abstract

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.

Enhancing the revelation of key genes and interaction networks in non‐small cell lung cancer with major depressive disorder: A bioinformatics analysis

“…The IL‐1β‐MAPK axis presents a promising therapeutic target for attenuating PD‐L1‐mediated suppression of antitumor immunity. 50 Besides, the axon guidance signaling pathway displayed the most prominent level of enrichment, consistently observed across all stress models and individuals diagnosed with MDD, 44 linked to changes in axon guidance molecules and their receptors, which could contribute to abnormalities in neural connectivity and communication. 51 Whereas, the interaction of the axon guidance factor Sema4D assumes a pivotal role in the formation of vasculogenic mimicry in NSCLC by activating the RhoA/ROCK pathway and regulating tumor cell plasticity and migration.…”

Adenosine increases PD‐L1 expression in mesenchymal stromal cells derived from cervical cancer through its interaction with A2AR/A2BR and the production of TGF‐β1

“…54 However, several additional TME-resident cytokines that can upregulate PD-L1 expression have been identified, including IL-1a, IL-10, IL-27, and IL-32g. 33,34,55,56 Similarly, there is evidence that TGF-β regulates the expression of PD-L1 in different tumor models [35][36][37] and that this cytokine promotes the enrichment of PD-L1 in exosomes derived from breast cancer tumor cells. 57 In the particular case of CeCa, the expression of PD-L1 is increased in LSIL and HSIL as well as in HR-HPV-positive CeCa, with PD-L1 considered a marker of poor prognosis.…”

IL-1β promotes esophageal squamous cell carcinoma growth and metastasis through FOXO3A by activating the PI3K/AKT pathway

“…IL-1β secreted by M1 macrophages can mediate the immune escape of tumor cells and thus play a pro-carcinogenic role by inducing the expression of the programmed cell death ligand PD-L1 in hepatocellular carcinoma [ 28 ]. IL-1β may also act synergistically with IFN-γ to promote maximal upregulation of PD-L1 in non-small cell lung cancer cells through activation of MAPK signaling thereby producing immunosuppressive effects [ 29 ]. EMT has been recognized as a key factor in the promotion of tumor metastasis, IL-1β and transforming growth factor β2 (TGF-β2) have been found to decrease epithelial cell markers and increase mesenchymal cell markers in normal human esophageal microvessel endothelial cells, enhancing cell proliferation and migration properties [ 30 ].…”