1. A modified HSV-1 oncolytic virus reconciles antiviral and antitumor immunity via promoting IFNβ expression and inhibiting PKR.
- Author
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Shen Y, Zhao X, Chen L, Wang X, Wang D, Zhang H, Zheng Z, Huang W, Zheng C, Chen Y, Chen C, and Chen Q
- Subjects
- Animals, Humans, Mice, Cell Line, Tumor, Neoplasms therapy, Neoplasms immunology, Neoplasms genetics, Oncolytic Virotherapy methods, Virus Replication, eIF-2 Kinase metabolism, eIF-2 Kinase genetics, Herpesvirus 1, Human genetics, Interferon-beta genetics, Interferon-beta metabolism, Oncolytic Viruses genetics
- Abstract
Type I interferon (IFN-I) is a potent immune modulator intricately involved in regulating tumor immunity. Meanwhile, the integrity of the IFN-I signaling pathway is essential for radiotherapy, chemotherapy, targeted therapy, and immunotherapy. However, the clinical application of IFN-I remains challenging due to its non-specific cytotoxicity and limited half-life. To overcome these limitations, we developed a gene delivery platform, CRISPR-V, enabling the rapid creation of novel HSV-1 oncolytic viruses. Utilizing this platform, we created an oncolytic virus, OVH-IFNβ, in which the IFNβ gene was incorporated into the HSV-1 genome. However, exogenous IFNβ expression significantly inhibited OVH-IFNβ replication. Through transcriptome data analyses, we identified several ISG genes inhibiting OVH-IFNβ replication. By gene knockout and functional studies of the downstream effectors, we confirmed the prominent antiviral activities of protein kinase R (PKR). To balance the antitumor and antiviral immunity of IFNβ, we developed a novel HSV-1 oncolytic virus, OVH-IFNβ-iPKR, which can express IFNβ while inhibiting PKR, leading to a potent antitumor immunity while reducing the antiviral capacity of IFNβ. OVH-IFNβ-iPKR shows a strong ability to induce immunogenic cell death and activate tumor-specific CD8
+ T cells, leading to de novo immune responses and providing a novel strategy for tumor immunotherapy., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024. Published by Elsevier B.V.)- Published
- 2024
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