The loss of RNA N6-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8+ T cell dysfunction and tumor growth

被引：197

作者：

Dong, Lihui ^{[1
]}

Chen, Chuanyuan ^{[2
,3
,4
]}

Zhang, Yawei ^{[2
,3
,4
]}

Guo, Peijin ^{[1
]}

Wang, Zhenghang ^{[5
]}

Li, Jian ^{[5
]}

Liu, Yi ^{[1
]}

Liu, Jun ^{[6
]}

Chang, Renbao ^{[2
,3
,4
]}

Li, Yilin ^{[1
]}

Liang, Guanghao ^{[2
,3
,4
]}

Lai, Weiyi ^{[7
]}

Sun, Mengxue ^{[1
]}

Dougherty, Urszula ^{[8
]}

Bissonnette, Marc B. ^{[8
]}

Wang, Hailin ^{[7
]}

Shen, Lin ^{[5
]}

Xu, Meng Michelle ^{[1
]}

Han, Dali ^{[2
,3
,4
,9
,10
]}

机构：

[1] Tsinghua Univ, THU PKU Ctr Life Sci, Sch Med, Inst Immunol,Dept Basic Med Sci,Beijing Key Lab I, Beijing 100084, Peoples R China

[2] Chinese Acad Sci, Key Lab Genom & Precis Med, Beijing Inst Genom, Beijing 100101, Peoples R China

[3] Chinese Acad Sci, China Natl Ctr Bioinformat, Beijing 100101, Peoples R China

[4] Univ Chinese Acad Sci, Coll Future Technol, Sino Danish Coll, Beijing 100049, Peoples R China

[5] Peking Univ Canc Hosp & Inst, Minist Educ, Key Lab Carcinogenesis & Translat Res, Dept Gastrointestinal Oncol, Beijing 100142, Peoples R China

[6] Peking Univ, Sch Life Sci, Beijing 100871, Peoples R China

[7] Chinese Acad Sci, Res Ctr Ecoenvironm Sci, State Key Lab Environm Chem & Ecotoxicol, Beijing 100085, Peoples R China

[8] Univ Chicago, Dept Med, Chicago, IL 60637 USA

[9] Chinese Acad Sci, Inst Stem Cell & Regenerat, Beijing 100101, Peoples R China

[10] China Natl Ctr Bioinformat, Beijing 100101, Peoples R China

来源：

CANCER CELL | 2021年 / 39卷 / 07期

基金：

北京市自然科学基金; 国家重点研发计划;

关键词：

NUCLEAR-RNA; TRANSLATION; MECHANISMS; EXHAUSTION; DYNAMICS; N6-METHYLADENOSINE; IMMUNOTHERAPY; DEMETHYLASE; EXPRESSION; RECEPTORS;

D O I：

10.1016/j.ccell.2021.04.016

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

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 N-6-methyladenosine (m(6)A) program and modulate tumor-infiltrating CD8(+) T cells by expressing multiple immunomodulatory ligands. Macrophage-specific knockout of an m(6)A 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 m(6)A 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-m(6)A 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 m(6)A methyltransferase in TAMs promotes CD8(+) T cell dysfunction and tumor progression.

引用

页码：945 / +

页数：23

共 86 条

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