Immunogenic HSV-mediated oncolysis shapes the antitumor immune response and contributes to therapeutic efficacy

Area of Science:

• Oncolytic virotherapy
• Immunology
• Virology

Background:

• The role of viral replication extent in oncolytic virus-mediated immune stimulation for tumor control is unclear.
• Herpes simplex virus (HSV) vectors are promising oncolytic agents, but their optimal design for potent antitumor activity requires further investigation.

Purpose of the Study:

• To investigate the essential features of oncolytic HSV for effective antitumor activity.
• To compare the in vitro and in vivo performance of infected cell protein 0 (ICP0)-defective HSV-1 and HSV-2 vectors.

Main Methods:

• Utilized ICP0-defective oncolytic Herpes simplex virus type 1 (HSV-1) and HSV-2 vectors (dICP0 and dNLS) with distinct replication and cytotoxicity profiles.
• Assessed in vitro replication, cytotoxicity, and in vivo tumor clearance, immune cell infiltration, and survival benefit in a tumor model.
• Quantified danger-associated molecular patterns (DAMPs), antigen-presenting cells (APCs), and antigen-specific CD8+ T-cell responses.

Main Results:

• HSV-2 vectors exhibited faster in vitro cytotoxicity but lower viral burst sizes than HSV-1 vectors.
• In vivo, both HSV-1 dICP0 and HSV-2 dICP0 replicated initially, but HSV-1 dICP0 was cleared more rapidly from tumors.
• Despite rapid clearance, HSV-1 dICP0 treatment significantly improved survival, correlating with increased DAMPs, APCs, and peripheral CD8+ T-cell responses.

Conclusions:

• Initial immunogenic replication of oncolytic HSV, rather than sustained viral presence, is crucial for activating antitumor immunity.
• These findings offer critical insights for designing more effective oncolytic HSV-based cancer therapies.