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Abstract：
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-1β (IL-1β) plays a key role in regulation of PD-L1 expression in non-small cell lung cancer (NSCLC).
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-1β in vitro to elucidate its induction of PD-L1 on NSCLC cells.
The 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.
Our 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.
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-1β in vitro to elucidate its induction of PD-L1 on NSCLC cells.
The 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.
Our 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.
摘要：
■程序性细胞死亡配体1（PD-L1）是一种生物标志物，用于预测免疫检查点抑制剂在各种癌症类型中的临床疗效。细胞因子在调节肿瘤细胞PD-L1表达中的作用尚未得到充分表征,however.在这里，我们发现白细胞介素-1β（IL-1β）在非小细胞肺癌（NSCLC）中PD-L1表达的调节中起关键作用。
我们使用可用的单细胞RNA序列数据对NSCLC组织中的细胞因子基因表达进行了综合筛选。然后，我们研究了IL-1β在体外的作用，以阐明其对PD-L1对NSCLC细胞的诱导作用。
■IL-1β基因在肿瘤微环境中高表达，特别是在巨噬细胞中。IL-1β和干扰素-γ(IFN-γ)的组合诱导NSCLC细胞系中PD-L1表达的协同增加。IL-1β和IFN-γ还协同激活丝裂原活化蛋白激酶（MAPK）信号，并促进下游转录因子与PD-L1基因启动子的结合。此外，MAPK信号抑制剂阻断IL-1β和IFN-γ对PD-L1的上调。
■我们的研究报告肿瘤微环境中高水平的IL-1β可能与IFN-γ协同作用，通过激活MAPK信号在肿瘤细胞中诱导最大的PD-L1表达，IL-1β-MAPK轴是减弱PD-L1介导的抗肿瘤免疫抑制的有希望的治疗靶标。
我们使用可用的单细胞RNA序列数据对NSCLC组织中的细胞因子基因表达进行了综合筛选。然后，我们研究了IL-1β在体外的作用，以阐明其对PD-L1对NSCLC细胞的诱导作用。
■IL-1β基因在肿瘤微环境中高表达，特别是在巨噬细胞中。IL-1β和干扰素-γ(IFN-γ)的组合诱导NSCLC细胞系中PD-L1表达的协同增加。IL-1β和IFN-γ还协同激活丝裂原活化蛋白激酶（MAPK）信号，并促进下游转录因子与PD-L1基因启动子的结合。此外，MAPK信号抑制剂阻断IL-1β和IFN-γ对PD-L1的上调。
■我们的研究报告肿瘤微环境中高水平的IL-1β可能与IFN-γ协同作用，通过激活MAPK信号在肿瘤细胞中诱导最大的PD-L1表达，IL-1β-MAPK轴是减弱PD-L1介导的抗肿瘤免疫抑制的有希望的治疗靶标。
