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Oncolytic Parapoxvirus induces Gasdermin E-mediated pyroptosis and activates antitumor immunity

Jing Lin1, Shihui Sun1, Kui Zhao1

  • 1Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 130062, Changchun, China.

Nature Communications
|January 14, 2023
PubMed

Insights

Oncolytic viruses (OVs) trigger tumor cell pyroptosis via Gasdermin E (GSDME), enhancing anti-tumor immunity. This mechanism is crucial for OV virotherapy success and sensitizing cold tumors to immunotherapy.

Area of Science:

  • Oncology
  • Virology
  • Immunology

Background:

  • Oncolytic viruses (OVs) offer dual anti-cancer effects: direct tumor cell lysis and immune stimulation.
  • Apoptosis, a common OV-induced cell death, is immunologically inert and doesn't fully explain inflamed tumor microenvironments.

Purpose of the Study:

  • To investigate the cell death mechanism induced by Oncolytic parapoxvirus ovis (ORFV) in tumors.
  • To determine the role of Gasdermin E (GSDME) in ORFV-mediated anti-tumor immunity and virotherapy efficacy.

Main Methods:

  • ORFV challenge of tumor cells and in vivo tumor models.
  • Analysis of cell death pathways, GSDME expression, ubiquitination, and pyroptosis.
  • Assessment of intratumoral cytotoxic T lymphocytes and tumor growth inhibition.

Main Results:

  • ORFV induces tumor cell pyroptosis mediated by Gasdermin E (GSDME).
  • ORFV pre-stabilizes GSDME in low-GSDME expressing cells, promoting pyroptosis.
  • GSDME depletion reduces pyroptotic cell death, cytotoxic T lymphocyte infiltration, and ORFV virotherapy success.

Conclusions:

  • GSDME-mediated pyroptosis is critical for ORFV-induced anti-tumor immunity.
  • ORFV virotherapy efficacy is dependent on GSDME.
  • ORFV sensitizes "cold" tumors to checkpoint blockade, suggesting combinatorial therapy strategies.

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