m 6 A RNA methyltransferases METTL3/14 regulate immune responses to anti‐PD‐1 therapy

• DOI: 10.15252/embj.2020104514
• Publication Date: 2020-09-23T09:32:06Z
• Authors: Lingling Wang; Hui Hui; Kriti Agrawal; Yuqi Kang; Na Li; Rachel Tang; Jiajun Yuan; Tariq M Rana
• Keywords: 0301 basic medicine; Mice, Inbred BALB C; Adenosine; Articles; Methyltransferases; CD8-Positive T-Lymphocytes; Chemokine CXCL9; Immunohistochemistry; 3. Good health; Chemokine CXCL10; Mice, Inbred C57BL; Interferon-gamma; Mice; 03 medical and health sciences; Cell Line, Tumor; Animals; Cytokines; Humans; Immunotherapy; Colorectal Neoplasms; Immune Checkpoint Inhibitors; Melanoma; Cell Proliferation; Interferon Regulatory Factor-1

An impressive clinical success has been observed in treating a variety of cancers using immunotherapy with programmed cell death-1 (PD-1) checkpoint blockade. However, limited response in most patients treated with anti-PD-1 antibodies remains a challenge, requiring better understanding of molecular mechanisms limiting immunotherapy. In colorectal cancer (CRC) resistant to immunotherapy, mismatch-repair-proficient or microsatellite instability-low (pMMR-MSI-L) tumors have low mutation burden and constitute ~85% of patients. Here, we show that inhibition of N6 -methyladenosine (m6 A) mRNA modification by depletion of methyltransferases, Mettl3 and Mettl14, enhanced response to anti-PD-1 treatment in pMMR-MSI-L CRC and melanoma. Mettl3- or Mettl14-deficient tumors increased cytotoxic tumor-infiltrating CD8+ T cells and elevated secretion of IFN-γ, Cxcl9, and Cxcl10 in tumor microenvironment in vivo. Mechanistically, Mettl3 or Mettl14 loss promoted IFN-γ-Stat1-Irf1 signaling through stabilizing the Stat1 and Irf1 mRNA via Ythdf2. Finally, we found a negative correlation between METTL3 or METTL14 and STAT1 in 59 patients with pMMR-MSI-L CRC tumors. Altogether, our findings uncover a new awareness of the function of RNA methylation in adaptive immunity and provide METTL3 and METTL14 as potential therapeutic targets in anticancer immunotherapy.