CD59型
癌症研究
免疫检查点
下调和上调
生物
免疫系统
补体系统
Wnt信号通路
CD8型
免疫学
免疫疗法
细胞生物学
信号转导
生物化学
基因
作者
Fei Shao,Yibo Gao,Wei Wang,Haiyan He,Liwei Xiao,Xiao Geng,Yan Xia,Dong Guo,Jing Fang,Jie He,Zhimin Lu
出处
期刊:Nature cancer
[Springer Nature]
日期:2022-10-21
卷期号:3 (10): 1192-1210
被引量:24
标识
DOI:10.1038/s43018-022-00444-4
摘要
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.
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