journal contribution
posted on 2024-05-15, 07:21 authored by 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 Receiver operating characteristic curves analysis for NETs in HCC.
Funding
the National Key Research and Development Program of China
the National Scientific Foundation of China
China Postdoctoral Science Foundation (China Postdoctoral Foundation Project)
National Postdoctoral Program for Innovative Talents (Postdoctoral Innovation Talent Support Program of China)
Basic and Applied Basic Research Project of Guangzhou, Guangdong province, China
History
ARTICLE ABSTRACT
Neutrophil extracellular traps (NET), 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 antitumor immunity and thereby promote HCC progression. TGFβ1 induced NET formation, which recruited CD8+ T cells. Binding to NET-DNA inhibited CD8+ T cells function while increasing apoptosis and TGFβ1 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 NFκB 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. TGFβ1 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.
TMCO6 is a receptor for DNA of NETs that mediates CD8+ T-cell dysfunction in HCC, indicating that the NET-TMCO6 axis is a promising target for overcoming immunosuppression in liver cancer.
