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首页> 外文期刊>Cell biology international. >KRAS G12V mutation upregulates PD-L1 expression via TGF-beta/EMT signaling pathway in human non-small-cell lung cancer
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KRAS G12V mutation upregulates PD-L1 expression via TGF-beta/EMT signaling pathway in human non-small-cell lung cancer

机译：KRAS G12V突变通过人类非小细胞肺癌中的TGF-Beta / EMT信号通路推动PD-L1表达

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摘要

Although clinical data suggest remarkable promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small-cell lung cancer (NSCLC), it is still largely undetermined which subtype of patients will be responsive to checkpoint blockade. In the present study, we explored whether PD-L1 was regulated by mutant Kirsten rat sarcoma viral oncogene homolog (KRAS), which is frequently mutated in NSCLC and results in poor prognosis and low survival rates. We verified that PD-L1 levels were dramatically increased in KRAS mutant cell lines, particularly in NCI-H441 cells with KRAS G12V mutation. Overexpression of KRAS G12V remarkably elevated PD-L1 messenger RNA and protein levels, while suppression of KRAS G12V led to decreased PD-L1 levels in NCI-H441 cells. Consistently, higher levels of PD-L1 were observed in KRAS-mutated tissues as well as tumor tissues-derived CD4(+) and CD8(+) T cells using a tumor xenograft in B-NDG mice. Mechanically, both in vitro and in vivo assays found that KRAS G12V upregulated PD-L1 via regulating the progression of epithelial-to-mesenchymal transition (EMT). Moreover, pembrolizumab activated the antitumor activity and decreased tumor growth with KRAS G12V mutated NSCLC. This study demonstrates that KRAS G12V mutation could induce PD-L1 expression and promote immune escape via transforming growth factor-beta/EMT signaling pathway in KRAS-mutant NSCLC, providing a potential therapeutic approach for NSCLC harboring KRAS mutations.
机译：尽管临床数据表明，在非小细胞肺癌（NSCLC）中靶向程序性细胞死亡蛋白-1（PD-1）和配体（PD-L1）信号具有显著的前景，但在很大程度上仍不确定哪种亚型患者对检查点阻断有反应。在本研究中，我们探讨了PD-L1是否受突变Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）的调节，KRAS在NSCLC中经常发生突变，导致预后不良和低存活率。我们证实在KRAS突变细胞系中PD-L1水平显著升高，尤其是在具有KRAS G12V突变的NCI-H441细胞中。KRAS G12V的过度表达显著提高了PD-L1信使RNA和蛋白质水平，而KRAS G12V的抑制导致NCI-H441细胞中PD-L1水平降低。一致地，在B-NDG小鼠中使用肿瘤异种移植物在KRAS突变组织以及肿瘤组织衍生的CD4（+）和CD8（+）T细胞中观察到更高水平的PD-L1。在机械方面，体外和体内实验均发现KRAS G12V通过调节上皮-间质转化（EMT）的进展上调PD-L1。此外，彭布罗利珠单抗通过KRAS G12V突变的NSCLC激活抗肿瘤活性并降低肿瘤生长。本研究表明，KRAS G12V突变可通过转化生长因子β/EMT信号通路诱导PD-L1表达并促进KRAS突变NSCLC的免疫逃逸，为含有KRAS突变的NSCLC提供了一种潜在的治疗途径。

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  • 来源
    《Cell biology international.》 |2021年第4期|共9页
  • 作者

    Pan Li-Na; Ma Yun-Fang; Li Zhen; Hu Jia-An; Xu Zhi-Hong;

  • 作者单位

    Shanghai Jiao Tong Univ Ruijin Hosp Dept Geriatr 197 Ruijin Second Rd Shanghai 200025 Peoples;

    Shanghai Jiao Tong Univ Ruijin Hosp Dept Geriatr 197 Ruijin Second Rd Shanghai 200025 Peoples;

    Shanghai Jiao Tong Univ Ruijin Hosp Dept Geriatr 197 Ruijin Second Rd Shanghai 200025 Peoples;

    Shanghai Jiao Tong Univ Ruijin Hosp Dept Geriatr 197 Ruijin Second Rd Shanghai 200025 Peoples;

    Shanghai Jiao Tong Univ Ruijin Hosp Dept Geriatr 197 Ruijin Second Rd Shanghai 200025 Peoples;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞生物学;
  • 关键词

    immunotherapy; KRAS; NSCLC; PDamp; 8208; L1;

    机译：免疫疗法;KRA;NSCLC;PD＆amp;8208;L1;

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