m6 A RNA methyltransferases METTL3/14 regulate immune responses to anti-PD-1 therapy
- EMBO J. 2020 Oct 15;39(20):e104514. doi: 10.15252/embj.2020104514.
- 1. Division of Genetics, Department of Pediatrics, Program in Immunology, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
- 2. Bioinformatics Program, University of California San Diego, La Jolla, CA, USA.
- 3. San Diego Center for Precision Immunotherapy, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
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.