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Executioner caspases restrict mitochondrial RNA-driven Type I IFN induction during chemotherapy-induced apoptosis

Shane T Killarney1, Rachel Washart1, Ryan S Soderquist1

  • 1Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.

Nature Communications
|March 15, 2023
PubMed

Insights

During apoptosis, mitochondrial RNA (mtRNA) is released into the cytoplasm. Executioner caspases-3 and -7 normally prevent this mtRNA from causing inflammation, but inhibiting them can boost anti-tumor immunity.

Area of Science:

  • Cell Biology
  • Immunology
  • Cancer Research

Background:

  • Mitochondrial outer membrane permeabilization (MOMP) during apoptosis releases macromolecules.
  • The fate and role of mitochondrial RNA (mtRNA) during apoptosis remain unclear.

Purpose of the Study:

  • To investigate the release and function of mtRNA during apoptosis.
  • To determine the role of executioner caspases in regulating mtRNA-mediated signaling.
  • To explore the therapeutic potential of modulating this pathway in cancer.

Main Methods:

  • Investigated mtRNA release during MOMP.
  • Utilized genetic and pharmacological inhibition of caspases-3 and -7 (casp3/7).
  • Assessed activation of the MDA5/MAVS/IRF3 pathway and Type I interferon (IFN) signaling.
  • Evaluated anti-tumor immunity in immunologically cold cancer models.

Main Results:

  • MOMP leads to the cytoplasmic release of mtRNA.
  • Casp3/7 inhibit inflammatory signaling triggered by cytoplasmic mtRNA.
  • Inhibition of casp3/7 activates the MDA5/MAVS/IRF3 pathway, driving Type I IFN signaling.
  • This pathway enhances CD8+ T-cell-dependent anti-tumor immunity and overcomes anti-PD1 resistance.

Conclusions:

  • Caspases-3 and -7 play a crucial role in suppressing inflammation from released mtRNA.
  • Modulating casp3/7 activity can enhance the immunogenicity of chemotherapy-induced apoptosis.
  • Targeting this pathway offers a strategy to improve cancer immunotherapy outcomes.

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