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,C. L. Zhang,Shaoyan Cheng,Dijun Ouyang,Ping Yu,Jieying Yang,Yaojun Zhang,Yan Tang,Hao Chen,Q Wang,Y. Li,Jia He,Tong Xiang,Yizhuo Zhang,Jianchuan Xia
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-02-21
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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