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A modified HSV-1 oncolytic virus reconciles antiviral and antitumor immunity via promoting IFNß expression and inhibiting PKR.
Shen, Yangkun; Zhao, Xiangqian; Chen, Lizhu; Wang, Xin; Wang, Dawei; Zhang, Hucheng; Zheng, Zuda; Huang, Weiwei; Zheng, Chunfu; Chen, Yu; Chen, Chuanben; Chen, Qi.
Affiliation
  • Shen Y; Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China.
  • Zhao X; Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China.
  • Chen L; Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China.
  • Wang X; Fuzhou Hospital of Traditional Chinese Medicine Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, China.
  • Wang D; Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China.
  • Zhang H; Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China.
  • Zheng Z; Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China.
  • Huang W; Department of Medical Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China.
  • Zheng C; Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • Chen Y; Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China. Electronic address: chenyu1980@fjmu.edu.cn.
  • Chen C; Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China. Electronic address: ccb@fjmu.edu.cn.
  • Chen Q; Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China. Electronic address: chenqi@fjnu.edu.cn.
Int J Biol Macromol ; 274(Pt 2): 133297, 2024 Aug.
Article in En | MEDLINE | ID: mdl-38925170
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-IFNß, in which the IFNß gene was incorporated into the HSV-1 genome. However, exogenous IFNß expression significantly inhibited OVH-IFNß replication. Through transcriptome data analyses, we identified several ISG genes inhibiting OVH-IFNß 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 IFNß, we developed a novel HSV-1 oncolytic virus, OVH-IFNß-iPKR, which can express IFNß while inhibiting PKR, leading to a potent antitumor immunity while reducing the antiviral capacity of IFNß. OVH-IFNß-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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Interferon-beta / Herpesvirus 1, Human / EIF-2 Kinase / Oncolytic Viruses Limits: Animals / Humans Language: En Journal: Int J Biol Macromol Year: 2024 Document type: Article Affiliation country: China Country of publication: Netherlands

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Interferon-beta / Herpesvirus 1, Human / EIF-2 Kinase / Oncolytic Viruses Limits: Animals / Humans Language: En Journal: Int J Biol Macromol Year: 2024 Document type: Article Affiliation country: China Country of publication: Netherlands