1. The loss of RNA N6-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8+ T cell dysfunction and tumor growth
- Author
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Zhenghang Wang, Lin Shen, Yawei Zhang, Renbao Chang, Lihui Dong, Marc Bissonnette, Urszula Dougherty, Chuanyuan Chen, Yi Liu, Jian Li, Jun Liu, Hailin Wang, Meng Michelle Xu, Yilin Li, Weiyi Lai, Mengxue Sun, Peijin Guo, Guanghao Liang, and Dali Han
- Subjects
0301 basic medicine ,Cancer Research ,Tumor microenvironment ,Methyltransferase ,Chemistry ,medicine.medical_treatment ,EBI3 ,Tumor-associated macrophage ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Cytokine ,Oncology ,Tumor progression ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Cytotoxic T cell ,CD8 - Abstract
Summary 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.
- Published
- 2021
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