| First Author | Dong L | Year | 2021 |
| Journal | Cancer Cell | Volume | 39 |
| Issue | 7 | Pages | 945-957.e10 |
| PubMed ID | 34019807 | Mgi Jnum | J:313912 |
| Mgi Id | MGI:6720429 | Doi | 10.1016/j.ccell.2021.04.016 |
| Citation | Dong L, et al. (2021) The loss of RNA N(6)-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8(+) T cell dysfunction and tumor growth. Cancer Cell |
| abstractText | 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. |
