细胞毒性T细胞
癌症研究
CD8型
T细胞
生物
细胞生物学
免疫学
免疫系统
生物化学
体外
作者
Lihui Dong,Chuanyuan Chen,Wei Wang,Peijin Guo,Zhenghang Wang,Jian Li,Yi Liu,Jun Liu,Ronald Chang,Yilin Li,Guanghao Liang,Weiyi Lai,Mengxue Sun,Urszula Dougherty,Marc Bissonnette,Hailin Wang,Lin Shen,Meng Xu,Dali Han
出处
期刊:Cancer Cell
[Elsevier]
日期:2021-07-01
卷期号:39 (7): 945-957.e10
被引量:161
标识
DOI:10.1016/j.ccell.2021.04.016
摘要
Tumor-associated macrophages (TAMs) can dampen the antitumor activity of T cells, yet the underlying mechanism remains incompletely understood. Here, we show that C1q+ TAMs are regulated by an RNA N6-methyladenosine (m6A) program and modulate tumor-infiltrating CD8+ T cells by expressing multiple immunomodulatory ligands. Macrophage-specific knockout of an m6A methyltransferase Mettl14 drives CD8+ T cell differentiation along a dysfunctional trajectory, impairing CD8+ T cells to eliminate tumors. Mettl14-deficient C1q+ TAMs show a decreased m6A abundance on and a higher level of transcripts of Ebi3, a cytokine subunit. In addition, neutralization of EBI3 leads to reinvigoration of dysfunctional CD8+ T cells and overcomes immunosuppressive impact in mice. We show that the METTL14-m6A levels are negatively correlated with dysfunctional T cell levels in patients with colorectal cancer, supporting the clinical relevance of this regulatory pathway. Thus, our study demonstrates how an m6A methyltransferase in TAMs promotes CD8+ T cell dysfunction and tumor progression.
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