Oncolytic Vaccinia Virus Expressing HSP70 shRNA Exerts Anti-Tumor Effects in Human Ovarian Cancer via Triggering the...

Area of Science:

• Oncology
• Immunology
• Virology

Background:

• Heat shock protein 70 (HSP70) is a potential cancer therapy target.
• Oncolytic vaccinia virus (oncoVV) shows anti-tumor effects via oncolysis and immune activation.
• The therapeutic potential of HSP70-silenced oncoVV (oncoVV-shHSP70) is currently unknown.

Purpose of the Study:

• To investigate the anti-tumor efficacy of oncoVV-shHSP70 in ovarian cancer models.
• To elucidate the mechanisms underlying the enhanced anti-tumor activity of oncoVV-shHSP70.
• To evaluate oncoVV-shHSP70 as a potential viro-immunotherapy for solid tumors.

Main Methods:

• Utilized ovarian cancer cell lines, immunodeficient mice, and humanized mice models.
• Assessed tumor regression, apoptosis, autophagy flux, ROS generation, and immune cell infiltration.
• Analyzed viral replication and pro-inflammatory cytokine expression.
• Investigated T cell redistribution and cytotoxic T cell populations in humanized mice.

Main Results:

• oncoVV-shHSP70 demonstrated superior tumor regression compared to control oncoVV.
• HSP70 silencing enhanced apoptosis, autophagy flux, and ROS generation.
• An autophagy-ROS feedback loop amplified viral replication and cytokine production.
• oncoVV-shHSP70 promoted spatial redistribution of cytotoxic T cells, increasing tumor-infiltrating hCD8+hGZMB+ populations in humanized mice.

Conclusions:

• oncoVV-shHSP70 exhibits potent anti-tumor activity through enhanced oncolysis and immune reprogramming.
• The study reveals a novel autophagy-ROS feedback loop mechanism.
• oncoVV-shHSP70 represents a promising preclinical candidate for viro-immunotherapy in solid tumors, warranting further clinical investigation.