Targeting PRMT3 impairs methylation and oligomerization of HSP60 to boost anti-tumor immunity by activating cGAS/STING signaling

Nat Commun. 2024 Sep 10;15(1):7930. doi: 10.1038/s41467-024-52170-3.

Abstract

Immune checkpoint blockade (ICB) has emerged as a promising therapeutic option for hepatocellular carcinoma (HCC), but resistance to ICB occurs and patient responses vary. Here, we uncover protein arginine methyltransferase 3 (PRMT3) as a driver for immunotherapy resistance in HCC. We show that PRMT3 expression is induced by ICB-activated T cells via an interferon-gamma (IFNγ)-STAT1 signaling pathway, and higher PRMT3 expression levels correlate with reduced numbers of tumor-infiltrating CD8+ T cells and poorer response to ICB. Genetic depletion or pharmacological inhibition of PRMT3 elicits an influx of T cells into tumors and reduces tumor size in HCC mouse models. Mechanistically, PRMT3 methylates HSP60 at R446 to induce HSP60 oligomerization and maintain mitochondrial homeostasis. Targeting PRMT3-dependent HSP60 methylation disrupts mitochondrial integrity and increases mitochondrial DNA (mtDNA) leakage, which results in cGAS/STING-mediated anti-tumor immunity. Lastly, blocking PRMT3 functions synergize with PD-1 blockade in HCC mouse models. Our study thus identifies PRMT3 as a potential biomarker and therapeutic target to overcome immunotherapy resistance in HCC.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / immunology
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / pathology
  • Cell Line, Tumor
  • Chaperonin 60* / genetics
  • Chaperonin 60* / metabolism
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / immunology
  • DNA, Mitochondrial / metabolism
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / immunology
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • Male
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism
  • Methylation
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Nucleotidyltransferases* / genetics
  • Nucleotidyltransferases* / metabolism
  • Protein-Arginine N-Methyltransferases* / genetics
  • Protein-Arginine N-Methyltransferases* / metabolism
  • Signal Transduction*

Substances

  • Protein-Arginine N-Methyltransferases
  • Membrane Proteins
  • Nucleotidyltransferases
  • Chaperonin 60
  • Immune Checkpoint Inhibitors
  • STING1 protein, human
  • cGAS protein, human
  • DNA, Mitochondrial
  • Interferon-gamma