STING activator 2'3'-cGAMP enhanced HSV-1-based oncolytic viral therapy

Area of Science:

• Immunology
• Virology
• Cancer Therapy

Background:

• Oncolytic viruses (OVs) show promise for cancer treatment by selectively targeting tumor cells and enhancing anti-tumor immunity.
• Stimulator of Interferon Genes (STING)-interferon (IFN) pathway agonists activate dendritic cells (DCs) for anti-tumor benefits.
• The potential for STING-IFN pathway activation to inhibit OV replication has limited the exploration of combined therapies.

Purpose of the Study:

• To investigate the combined efficacy of an HSV-1 based OV (C-REV) and a membrane-impermeable STING agonist (2'3'-cGAMP) against tumors.
• To assess the impact of this combination therapy on the tumor microenvironment and systemic anti-tumor immune responses.

Main Methods:

• Utilized an HSV-1 based oncolytic virus (C-REV) and a STING agonist (2'3'-cGAMP).
• Evaluated the STING-IFN pathway's functionality in tumor cells.
• Assessed immune cell populations (CD8+ T-cells, DCs) in tumor sites and lymph nodes in vivo.
• Measured systemic anti-tumor immunity and immune memory responses.

Main Results:

• Tumor cells exhibited a defective STING-IFN pathway, limiting antiviral IFN induction.
• Combination therapy increased proliferative KLRG1-high PD1-low CD8+ T-cells and activated CD103+ DCs within the tumor.
• Elevated tumor-specific CD44+ CD8+ T-cells were observed in lymph nodes following combination treatment.
• The C-REV and 2'3'-cGAMP combination induced robust anti-tumor immune memory and enhanced systemic immunity.

Conclusions:

• The combination of C-REV and 2'3'-cGAMP effectively overcomes defects in the tumor cell STING-IFN pathway.
• This combination therapy significantly enhances systemic anti-tumor immunity and establishes immune memory.
• The findings support the potential of combining oncolytic viruses with STING agonists as a potent cancer immunotherapy strategy.