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PRMT1 mediated methylation of cGAS suppresses anti-tumor immunity

Jing Liu1,2,3,4, Xia Bu5, Chen Chu6,7

  • 1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.

Nature Communications
|May 16, 2023
PubMed

Insights

PRMT1 suppresses anti-tumor immunity by methylating cGAS. Inhibiting PRMT1 reactivates the cGAS/STING pathway, enhancing immune response and tumor therapy efficacy.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cancer Research

Background:

  • The cGAS/STING innate immunity pathway is crucial for anti-tumor immunotherapy.
  • Mechanisms of tumor-intrinsic cGAS signaling suppression remain unclear, hindering anti-cancer immune surveillance.

Purpose of the Study:

  • To investigate the role of PRMT1 in regulating cGAS signaling and tumor immunity.
  • To explore PRMT1 as a therapeutic target for enhancing anti-tumor responses.

Main Methods:

  • Investigated PRMT1's methylation of cGAS at Arg133.
  • Utilized genetic and pharmaceutical PRMT1 ablation in cancer models.
  • Assessed cGAS/STING pathway activation, interferon gene transcription, and tumor-infiltrating lymphocytes.
  • Evaluated combination therapy of PRMT1 inhibitor with anti-PD-1 antibody.

Main Results:

  • PRMT1 methylates cGAS, preventing dimerization and suppressing cGAS/STING signaling in cancer cells.
  • PRMT1 ablation activates cGAS/STING-dependent DNA sensing and upregulates interferon response genes.
  • PRMT1 inhibition increases cGAS-dependent tumor-infiltrating lymphocytes and PD-L1 expression.
  • Combination therapy with PRMT1 inhibitor and anti-PD-1 antibody shows augmented anti-tumor efficacy.

Conclusions:

  • PRMT1 acts as a negative regulator of cGAS/STING signaling in cancer.
  • The PRMT1/cGAS/PD-L1 axis is a key determinant of immune surveillance.
  • Targeting PRMT1 offers a promising strategy to boost anti-tumor immunity.

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