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m6 A RNA methyltransferases METTL3/14 regulate immune responses to anti-PD-1 therapy

Lingling Wang1, Hui Hui1,2, Kriti Agrawal1,2

  • 1Division of Genetics, Department of Pediatrics, Program in Immunology, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.

The EMBO Journal
|September 23, 2020
PubMed

Insights

Inhibiting RNA methylation (m6 A) via METTL3/14 depletion boosts anti-PD-1 cancer immunotherapy response. This approach enhances T-cell activity and cytokine production in resistant tumors, offering new therapeutic targets.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Immunotherapy using PD-1 checkpoint blockade shows clinical success but has limited response rates in many cancer patients.
  • Mismatch-repair-proficient/microsatellite instability-low (pMMR-MSI-L) colorectal cancer (CRC) represents ~85% of cases and is often resistant to immunotherapy due to low mutation burden.

Purpose of the Study:

  • To investigate the role of N6 -methyladenosine (m6 A) mRNA modification in immunotherapy resistance.
  • To explore the potential of targeting m6 A methyltransferases (METTL3/14) to enhance anti-PD-1 treatment efficacy in pMMR-MSI-L CRC and melanoma.

Main Methods:

  • Depletion of methyltransferases Mettl3 and Mettl14 in pMMR-MSI-L CRC and melanoma models.
  • Analysis of tumor-infiltrating immune cells, cytokine secretion (IFN-γ, Cxcl9, Cxcl10), and the IFN-γ-Stat1-Irf1 signaling pathway.
  • Correlation analysis of METTL3/14 and STAT1 expression in patient tumor samples.

Main Results:

  • Depletion of Mettl3 or Mettl14 significantly enhanced the response to anti-PD-1 therapy in pMMR-MSI-L CRC and melanoma.
  • Mettl3/14 deficiency led to increased cytotoxic CD8+ T cells and elevated IFN-γ, Cxcl9, and Cxcl10 levels in the tumor microenvironment.
  • Loss of Mettl3/14 stabilized Stat1 and Irf1 mRNA, promoting IFN-γ-Stat1-Irf1 signaling, with a negative correlation observed between METTL3/14 and STAT1 in CRC patients.

Conclusions:

  • Inhibition of m6 A mRNA modification by targeting METTL3 and METTL14 can overcome resistance to anti-PD-1 immunotherapy.
  • METTL3 and METTL14 play a crucial role in regulating adaptive immunity and T-cell responses within the tumor microenvironment.
  • METTL3 and METTL14 represent promising therapeutic targets for improving anticancer immunotherapy outcomes, particularly in pMMR-MSI-L CRC.
Keywords:
CD8+ T cellscolorectal carcinomaimmunotherapym6A methylation

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