Oncolytic virus-delivered GSDME: Unlocking pyroptosis to improve dendritic cell function and amplify cytotoxic T cell...

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Oncolytic virotherapy shows promise for advanced cancers but faces limitations.
• Combining oncolytic viruses with immunogenic cell death, like pyroptosis, can enhance anti-tumor immunity.
• Pyroptosis, mediated by gasdermin proteins, releases damage-associated molecular patterns, amplifying immune responses.

Purpose of the Study:

• To engineer a chimeric Vesicular stomatitis virus (VSV)-GP to express Gasdermin E (GSDME) for pyroptosis induction in GSDME-deficient tumors.
• To evaluate the efficacy of the engineered VSV-GP-GSDME in inducing pyroptosis and enhancing anti-tumor immunity.

Main Methods:

• Engineered VSV-GP to express full-length GSDME.
• Assessed pyroptosis induction and cell death mechanisms in vitro.
• Evaluated tumor control, survival, and immune cell activation in vivo.

Main Results:

• VSV-GP-GSDME efficiently delivered GSDME to tumor cells, inducing caspase-3-dependent pyroptotic cell death.
• In vitro studies showed a shift from apoptosis to pyroptosis, enhancing tumor cell immunogenicity.
• In vivo studies demonstrated improved tumor control, prolonged survival, and enhanced anti-tumor immune responses, including dendritic cell activation and CD8 T cell expansion.

Conclusions:

• VSV-GP-GSDME effectively combines oncolytic activity with GSDME-mediated pyroptosis to induce potent anti-tumor immunity.
• This dual mechanism offers a promising strategy to enhance immunogenicity and broaden applicability across diverse tumors.
• The engineered virus presents a novel therapeutic approach for advanced cancers by leveraging pyroptosis to stimulate immune responses.