The loss of RNA N 6-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8 + T cell dysfunction and tumor growth

Cancer Cell. 2021 Jul 12;39(7):945-957.e10. doi: 10.1016/j.ccell.2021.04.016. Epub 2021 May 20.

Abstract

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.

Keywords: EBI3; METTL14; T cell dysfunction; m(6)A epi-transcriptome; tumor microenvironment; tumor-associated macrophage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemistry
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • Carcinoma, Lewis Lung / immunology
  • Carcinoma, Lewis Lung / metabolism
  • Carcinoma, Lewis Lung / pathology
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Cytokines / metabolism
  • Female
  • Humans
  • Lymphocyte Activation / immunology*
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology
  • Methyltransferases / genetics
  • Methyltransferases / metabolism*
  • Methyltransferases / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Minor Histocompatibility Antigens / metabolism
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Receptors, Cytokine / metabolism
  • Tumor Microenvironment
  • Tumor-Associated Macrophages / metabolism*
  • Tumor-Associated Macrophages / pathology

Substances

  • Cytokines
  • Ebi3 protein, mouse
  • Minor Histocompatibility Antigens
  • Receptors, Cytokine
  • N(6)-ribosyladenine
  • METTL14 protein, human
  • Methyltransferases
  • Mettl14 protein, mouse
  • Adenosine