Department of Basic Medical Sciences, School of Medicine, Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, THU-PKU Center for Life Sciences, Tsinghua University, Beijing 100084, China.
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, and China National Center for Bioinformation, Chinese Academy of Sciences, Beijing 100101, China; College of Future Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, China.
Cancer Cell. 2021 Jul 12;39(7):945-957.e10. doi: 10.1016/j.ccell.2021.04.016. Epub 2021 May 20.
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-methyladenosine (mA) program and modulate tumor-infiltrating CD8 T cells by expressing multiple immunomodulatory ligands. Macrophage-specific knockout of an mA 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 mA 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-mA 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 mA methyltransferase in TAMs promotes CD8 T cell dysfunction and tumor progression.
肿瘤相关巨噬细胞（TAMs）可抑制 T 细胞的抗肿瘤活性，但潜在机制尚不完全清楚。在这里，我们表明 C1q TAMs 受 RNA N6-甲基腺苷（m6A）调控，并通过表达多种免疫调节配体来调节肿瘤浸润的 CD8 T 细胞。巨噬细胞特异性敲除 m6A 甲基转移酶 Mettl14 会沿着功能失调的轨迹驱动 CD8 T 细胞分化，从而损害 CD8 T 细胞消除肿瘤的能力。缺乏 Mettl14 的 C1q TAMs 在 Ebi3（一种细胞因子亚基）上的 m6A 丰度降低，转录水平升高。此外，中和 EBI3 会重新激活功能失调的 CD8 T 细胞，并在小鼠中克服免疫抑制的影响。我们表明，结直肠癌患者中 METTL14-m6A 水平与功能失调的 T 细胞水平呈负相关，支持了这种调控途径的临床相关性。因此，我们的研究表明 TAMs 中的 m6A 甲基转移酶如何促进 CD8 T 细胞功能障碍和肿瘤进展。
