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

Abstract

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.

• Authors: Lihui Dong, Chuanyuan Chen, Yawei Zhang, Peijin Guo, Zhenghang Wang, Jian Li, Yi Liu, Jun Liu, Renbao Chang, Yilin Li, Guanghao Liang, Weiyi Lai, Mengxue Sun, Urszula Dougherty, Marc B Bissonnette, Hailin Wang, Lin Shen, Meng Michelle Xu, Dali Han
• Journal: Cancer cell (Cancer Cell) Vol. 39 Issue 7 Pg. 945-957.e10 (07 12 2021) ISSN: 1878-3686 [Electronic] United States
• PMID: 34019807 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• Ebi3 protein, mouse
• Minor Histocompatibility Antigens
• Receptors, Cytokine
• N(6)-ribosyladenine
• METTL14 protein, human
• Methyltransferases
• Mettl14 protein, mouse
• Adenosine

Topics

• Adenosine (analogs & derivatives, chemistry)
• Animals
• CD8-Positive T-Lymphocytes (immunology)
• Carcinoma, Lewis Lung (immunology, metabolism, pathology)
• Colorectal Neoplasms (immunology, metabolism, pathology)
• Cytokines (metabolism)
• Female
• Humans
• Lymphocyte Activation (immunology)
• Melanoma, Experimental (immunology, metabolism, pathology)
• Methyltransferases (genetics, metabolism, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Minor Histocompatibility Antigens (metabolism)
• Neoplasms (immunology, metabolism, pathology)
• Receptors, Cytokine (metabolism)
• Tumor Microenvironment
• Tumor-Associated Macrophages (metabolism, pathology)