沉默 EGFR 上调的 CD55 和 CD59 表达可激活补体系统并使肺癌对检查点阻断敏感,Nature Cancer

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沉默 EGFR 上调的 CD55 和 CD59 表达可激活补体系统并使肺癌对检查点阻断敏感
Nature Cancer ( IF 23.5 ) Pub Date : 2022-10-21 , DOI: 10.1038/s43018-022-00444-4
Fei Shao _{1,

2,

3} , Yibo Gao _{1,

3,

4,

5} , Wei Wang _{1,

6} , Haiyan He ₇ , Liwei Xiao ₇ , Xiao Geng ₁ , Yan Xia ₈ , Dong Guo ₇ , Jing Fang ₂ , Jie He _{1,

4} , Zhimin Lu _{7,

8,

9}

Affiliation

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
The Affiliated Hospital of Qingdao University, Qingdao University, and Qingdao Cancer Institute, Qingdao, China.
Laboratory of Translational Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China.
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Department of Neuro-Oncology, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Zhejiang University Cancer Center, Zhejiang University, Hangzhou, China.

补体系统是一种重要的免疫成分，但其在肿瘤免疫逃避和 CD8 ⁺ T 细胞激活中的作用尚不清楚。在这里，我们证明表皮生长因子受体 (EGFR)/Wnt 信号诱导 β-连环蛋白介导的长链非编码 RNA (lncRNA) LINC00973 表达至海绵 CD55 靶向 miR-216b 和 CD59 靶向 miR-150。^{因此上调的 CD55/CD59 表达抑制了 CD8 +} T 细胞活化所需的补体系统和细胞因子分泌。CD55/CD59中和抗体处理或LINC00973启动子突变激活补体和CD8 ⁺T 细胞，抑制肿瘤生长。重要的是，联合抗 CD55/CD59 和抗程序性死亡 1（抗 PD-1）抗体治疗可产生协同肿瘤抑制作用。此外，CD55/CD59 水平与人肺癌标本中 M1 巨噬细胞和 CD8 ^{+ T 细胞的浸润呈负相关，并可预测患者的预后。}这些发现强调了 EGFR/Wnt/β-catenin 上调 CD55/CD59 表达在抑制补体和 CD8 ⁺ T 细胞活化以实现肿瘤免疫逃避和免疫检查点阻断抵抗方面的关键作用，并确定了一种潜在的联合疗法来克服这些影响。

"点击查看英文标题和摘要"

Silencing EGFR-upregulated expression of CD55 and CD59 activates the complement system and sensitizes lung cancer to checkpoint blockade

The complement system is a critical immune component, yet its role in tumor immune evasion and CD8⁺ T cell activation is not clearly defined. Here, we demonstrate that epidermal growth factor receptor (EGFR)/Wnt signaling induces β-catenin-mediated long noncoding RNA (lncRNA) LINC00973 expression to sponge CD55-targeting miR-216b and CD59-targeting miR-150. The consequently upregulated CD55/CD59 expression suppresses the complement system and cytokine secretion required for CD8⁺ T cell activation. CD55/CD59-neutralizing antibody treatment or mutation of the LINC00973 promoter activates the complement and CD8⁺ T cells, inhibiting tumor growth. Importantly, combined anti-CD55/CD59 and anti-programmed death 1 (anti-PD-1) antibody treatments elicit a synergistic tumor-inhibiting effect. In addition, CD55/CD59 levels are inversely correlated with infiltration of M1 macrophages and CD8⁺ T cells in human lung cancer specimens and predict patient outcome. These findings underscore the critical role of EGFR/Wnt/β-catenin-upregulated CD55/CD59 expression in inhibiting the complement and CD8⁺ T cell activation for tumor immune evasion and immune checkpoint blockade resistance and identify a potential combination therapy to overcome these effects.

更新日期：2022-10-22

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