The loss of RNA N6-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8+ T cell dysfunction and tumor growth
The loss of RNA N6-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8+ T cell dysfunction and tumor growth
复制标题
DOI：
10.1016/j.ccell.2021.04.016
复制
发表时间：
2021-07-12
期刊：
影响因子：
50.3
通讯作者：
Han, Dali
中科院分区：
文献类型：
--
作者：
Dong, Lihui;Chen, Chuanyuan;Han, Dali
肿瘤相关巨噬细胞（TAM）可以抑制T细胞的抗肿瘤活性，但其潜在机制仍不完全清楚。在这里，我们发现C1 q（+）TAM受RNA N-6-甲基腺苷（m（6）A）程序的调节，并通过表达多种免疫调节配体来调节肿瘤浸润性CD 8（+）T细胞。巨噬细胞特异性敲除m（6）A甲基转移酶Mettl 14驱动CD 8（+）T细胞分化沿着功能失调的轨迹，损害CD 8（+）T细胞以消除肿瘤。Mettl 14缺陷型C1 q（+）TAM显示出降低的m（6）A丰度和更高水平的Ebi 3（细胞因子亚基）转录物。此外，EBI 3的中和导致功能失调的CD 8（+）T细胞的复苏，并克服了小鼠的免疫抑制作用。我们发现结直肠癌患者的胃L14-m（6）A水平与功能失调的T细胞水平呈负相关，支持了这种调节途径的临床相关性。因此，我们的研究证明了TAM中的m（6）A甲基转移酶如何促进CD 8（+）T细胞功能障碍和肿瘤进展。
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.