期刊
CANCER CELL
卷 39, 期 7, 页码 945-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2021.04.016
关键词
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资金
- National Key R&D Program of China [2018YFA0109700]
- Strategic Priority Research Program [XDA16010115]
- National Science Fund for Excellent Young Scholars [81922054, 31922017]
- Beijing Natural Science Foundation [Z200023, Z190016]
- Key Research Program of Frontier Sciences, Chinese Academy of Sciences [ZDBS-LY-SM013]
- CAS Hundred Talent Program
The study reveals that the m(6)A methyltransferase Mettl14 in TAMs plays a role in modulating the function of CD8(+) T cells by regulating C1q(+) TAMs, ultimately affecting tumor progression.
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.
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