RAS-Mitogen-Activated Protein Kinase Signal Is Required for Enhanced PD-L1 Expression in Human Lung Cancers.
RAS-Mitogen-Activated Protein Kinase Signal Is Required for Enhanced PD-L1 Expression in Human Lung Cancers.
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DOI：
10.1371/journal.pone.0166626
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Daigo Y
中科院分区：
文献类型：
--
作者：
Sumimoto H;Takano A;Teramoto K;Daigo Y
非小细胞肺癌（NSCLC）中异位程序性细胞死亡配体1（PD-L1）的表达与癌症的免疫逃避有关，是免疫检查点疗法的分子靶点。尽管 NSCLC 中的一些信号改变导致 PD-L1 异位表达，但其确切机制仍不清楚。由于我们发现 PD-L1 高表达的 NSCLC 细胞系中 EGFR/KRAS 突变的频率较高 (p < 0.001)，因此我们评估了下游信号与 PD-L1 表达之间的关系，特别是在三种 KRAS 突变腺癌细胞系中。与二甲亚砜相比，MEK 抑制剂 U0126 (20 μM) 显着降低表面 PD-L1 水平 50-60% (p < 0.0001)。佛波醇 12-肉豆蔻酸酯 13-乙酸酯刺激（100 nM，15 分钟）增加 (p < 0.05)，两种 ERK2 siRNA 以及 KRAS siRNA 减少 (p < 0.05) PD-L1 表达。通过荧光素酶测定证明了 PD-L1 基因中潜在 AP-1 位点（距转录起始位点 +4785 至 +5056）的转录活性，该活性被 U0126 抑制。染色质免疫沉淀测定证明了 cJUN 与 AP-1 位点的结合。在三种 KRAS 突变肺腺癌细胞系中的两种中，两种 STAT3 siRNA 使 PD-L1 表达降低 10-32% (p < 0.05)，而 PI3K 抑制剂 LY294002 (40 μM) 没有改变表达水平。 PD-L1 高和低 NSCLC 之间的监督聚类分析和基因集富集分析揭示了 PD-L1 表达与细胞运动/粘附相关基因/通路之间的相关性。这些结果表明MAPK信号是负责异位PD-L1表达的主要下游信号，STAT3也在一定程度上参与其中。此外，MAPK 信号传导可能控制 PD-L1 和一些与增强细胞运动性相关的基因的表达。我们的研究结果表明，MAPK 与 STAT3 一起对于确定 PD-L1 表达非常重要，这可能有助于肺癌的靶向治疗。
Ectopic programmed cell death ligand 1 (PD-L1) expression in non-small cell lung cancers (NSCLCs) is related to immune evasion by cancer, and it is a molecular target of immune checkpoint therapies. Although some altered signals in NSCLCs are responsible for ectopic PD-L1 expression, the precise mechanisms remain obscure. Because we found a higher frequency of EGFR/KRAS mutations in NSCLC cell lines with high PD-L1 expression (p < 0.001), we evaluated the relationships between downstream signals and PD-L1 expression, particularly in three KRAS-mutant adenocarcinoma cell lines. The MEK inhibitor U0126 (20 μM) significantly decreased the surface PD-L1 levels by 50–60% compared with dimethyl sulfoxide (p < 0.0001). Phorbol 12-myristate 13-acetate stimulation (100 nM, 15 min) increased (p < 0.05) and two ERK2 siRNAs as well as KRAS siRNAs decreased (p < 0.05) PD-L1 expression. The transcriptional activity of the potential AP-1 site (+4785 to +5056 from the transcription start site) in the PD-L1 gene was demonstrated by luciferase assays, which was inhibited by U0126. The chromatin immunoprecipitation assay demonstrated the binding of cJUN to the AP-1 site. Two STAT3 siRNAs decreased PD-L1 expression by 10–32% in two of the three KRAS-mutant lung adenocarcinoma cell lines (p < 0.05), while the PI3K inhibitor LY294002 (40 μM) did not change the expression level. Supervised cluster analysis and gene set enrichment analysis between the PD-L1-high and -low NSCLCs revealed a correlation between PD-L1 expression and genes/pathways related to cell motility/adhesion. These results indicate that MAPK signaling is the dominant downstream signal responsible for ectopic PD-L1 expression, in which STAT3 is also involved to some extent. Furthermore, MAPK signaling may control the expression of PD-L1 and several genes related to enhanced cell motility. Our findings suggest that MAPK, along with STAT3, is important for determining PD-L1 expression, which could be useful for targeted therapies against lung cancers.
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