中性粒细胞胞外陷阱
CD8型
肿瘤进展
生物
颗粒酶B
免疫学
细胞毒性T细胞
癌症研究
细胞生物学
遗传学
癌症
免疫系统
炎症
生物化学
体外
作者
Mengjia Song,Chaoqi Zhang,Shaoyan Cheng,Dijun Ouyang,Yu Ping,Jieying Yang,Yaojun Zhang,Yan Tang,Hao Chen,Qi-jing Wang,Yong-qiang Li,Jia He,Tong Xiang,Yizhuo Zhang,Jian‐Chuan Xia
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-02-21
被引量:1
标识
DOI:10.1158/0008-5472.can-23-2986
摘要
Abstract Neutrophil extracellular traps (NETs), formed by the extracellular release of decondensed chromatin and granules, have been shown to promote tumor progression and metastasis. Tumor-associated neutrophils in hepatocellular carcinoma (HCC) are prone to NET formation, highlighting the need for a more comprehensive understanding of the mechanisms of action of NETs in liver cancer. Here, we showed that DNA of NETs (NET-DNA) binds transmembrane and coiled-coil domains 6 (TMCO6) on CD8+ T cells to impair anti-tumor immunity and thereby promote HCC progression. TGF-β1 induced NET formation, which recruited CD8+ T cells. Binding to NET-DNA inhibited CD8+ T cells function while increasing apoptosis and TGF-β1 secretion, forming a positive feedback loop to further stimulate NET formation and immunosuppression. Mechanistically, the N-terminus of TMCO6 interacted with NET-DNA and suppressed T-cell receptor signaling and NF-κB p65 nuclear translocation. Blocking NET formation by inhibiting PAD4 induced potent antitumor effects in wild-type mice but not TMCO6-/- mice. In clinical samples, CD8+ T cells expressing TMCO6 had an exhausted phenotype. TGF-β1-signaling inhibition or TMCO6 deficiency combined with anti-PD-1 abolished NET-driven HCC progression in vivo. Collectively, this study unveils the role of NET-DNA in impairing CD8+ T-cell immunity by binding TMCO6 and identifies targeting this axis as an immunotherapeutic strategy for blocking HCC progression.
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