致癌 KRAS 信号通过激活 CD47 驱动肺腺癌先天免疫监视的逃避,The Journal of Clinical Investigation

当前位置： X-MOL 学术 › J. Clin. Invest. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

致癌 KRAS 信号通过激活 CD47 驱动肺腺癌先天免疫监视的逃避
The Journal of Clinical Investigation ( IF 13.3 ) Pub Date : 2023 , DOI: 10.1172/jci153470
Huanhuan Hu _{1,

2} , Rongjie Cheng _{1,

3} , Yanbo Wang _{1,

2} , Xiaojun Wang ₄ , Jianzhuang Wu ₁ , Yan Kong ₁ , Shoubin Zhan ₁ , Zhen Zhou ₁ , Hongyu Zhu ₁ , Ranran Yu ₁ , Gaoli Liang ₁ , Qingyan Wang ₁ , Xiaoju Zhu ₁ , Chen-Yu Zhang _{1,

5,

6} , Rong Yin _{4,

7,

8} , Chao Yan _{1,

2,

6} , Xi Chen _{1,

2,

5,

6,

9}

Affiliation

State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, and.
Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China.
Cancer Stem Cell Laboratory, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom.
Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital and Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China.
Research Unit of Extracellular RNA, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China.
Institute of Artificial Intelligence Biomedicine, Nanjing University, Nanjing, China.
Biobank of Lung Cancer, Jiangsu Biobank of Clinical Resources, Nanjing, China.
Collaborative Innovation Centre for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China.

KRAS是人类癌症中最常被激活的致癌基因之一。尽管KRAS突变在肿瘤发生和肿瘤维持中的作用已得到广泛研究，但 KRAS 与肿瘤免疫微环境之间的关系尚不完全清楚。在这里，我们确定了 KRAS 在驱动肿瘤逃避先天免疫监视方面的作用。来自患者和Kras的肺腺癌样本在肺癌基因小鼠模型中，突变体 KRAS 激活了分化簇 47 (CD47) 的表达，这是癌细胞中的一种抗吞噬信号，导致巨噬细胞对癌细胞的吞噬作用降低。从机制上讲，突变体 KRAS 激活 PI3K/STAT3 信号，从而抑制 miR-34a 表达并减轻 miR-34a 对 CD47 的转录后抑制。在 3 个独立的肺癌患者队列中，KRAS突变状态与 CD47 表达呈正相关。在治疗上， KRAS siRNA KRAS ^G12C破坏 KRAS/CD47 信号轴抑制剂 AMG 510 或 miR-34a 模拟物抑制 CD47 表达，增强巨噬细胞的吞噬能力，并恢复先天免疫监视。我们的结果揭示了活性 KRAS 与先天免疫逃避之间的直接机制联系，并将 CD47 鉴定为 KRAS 介导的免疫抑制肿瘤微环境的主要效应因子。

"点击查看英文标题和摘要"

Oncogenic KRAS signaling drives evasion of innate immune surveillance in lung adenocarcinoma by activating CD47

KRAS is one of the most frequently activated oncogenes in human cancers. Although the role of KRAS mutation in tumorigenesis and tumor maintenance has been extensively studied, the relationship between KRAS and the tumor immune microenvironment is not fully understood. Here, we identified a role of KRAS in driving tumor evasion from innate immune surveillance. In samples of lung adenocarcinoma from patients and Kras-driven genetic mouse models of lung cancer, mutant KRAS activated the expression of cluster of differentiation 47 (CD47), an antiphagocytic signal in cancer cells, leading to decreased phagocytosis of cancer cells by macrophages. Mechanistically, mutant KRAS activated PI3K/STAT3 signaling, which restrained miR-34a expression and relieved the posttranscriptional repression of miR-34a on CD47. In 3 independent cohorts of patients with lung cancer, the KRAS mutation status positively correlated with CD47 expression. Therapeutically, disruption of the KRAS/CD47 signaling axis with KRAS siRNA, the KRAS^G12C inhibitor AMG 510, or a miR-34a mimic suppressed CD47 expression, enhanced the phagocytic capacity of macrophages, and restored innate immune surveillance. Our results reveal a direct mechanistic link between active KRAS and innate immune evasion and identify CD47 as a major effector underlying the KRAS-mediated immunosuppressive tumor microenvironment.

更新日期：2023-01-18

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文