2. Academic Validation
  3. The potential of swine pseudorabies virus attenuated vaccine for oncolytic therapy against malignant tumors

The potential of swine pseudorabies virus attenuated vaccine for oncolytic therapy against malignant tumors

  • J Exp Clin Cancer Res. 2023 Oct 27;42(1):284. doi: 10.1186/s13046-023-02848-1.
Guosong Wang # 1,  Jiali Cao # 2,  Mengxuan Gui # 1,  Pengfei Huang # 1,  Liang Zhang # 1,  Ruoyao Qi 1,  Ruiqi Chen 1,  Lina Lin 1,  Qiangyuan Han 1,  Yanhua Lin 1,  Tian Chen 1,  Peiqing He 1,  Jian Ma 1,  Rao Fu 1,  Junping Hong 1,  Qian Wu 1,  Hai Yu 1,  Junyu Chen 1,  Chenghao Huang 3,  Tianying Zhang 4,  Quan Yuan 5,  Jun Zhang 6,  Yixin Chen 7,  Ningshao Xia 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic ProductsNational Innovation Platform for Industry-Education Intergration in Vaccine ResearchSchool of Life Sciences, School of Public Health, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, People's Republic of China.
  • 2 Department of Laboratory Medicine, Fujian Key Clinical Specialty of Laboratory Medicine, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, People's Republic of China.
  • 3 State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic ProductsNational Innovation Platform for Industry-Education Intergration in Vaccine ResearchSchool of Life Sciences, School of Public Health, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, People's Republic of China. huangchenghao@xmu.edu.cn.
  • 4 State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic ProductsNational Innovation Platform for Industry-Education Intergration in Vaccine ResearchSchool of Life Sciences, School of Public Health, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, People's Republic of China. tyzhang1003@163.com.
  • 5 State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic ProductsNational Innovation Platform for Industry-Education Intergration in Vaccine ResearchSchool of Life Sciences, School of Public Health, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, People's Republic of China. yuanquan@xmu.edu.cn.
  • 6 State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic ProductsNational Innovation Platform for Industry-Education Intergration in Vaccine ResearchSchool of Life Sciences, School of Public Health, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, People's Republic of China. zhangj@xmu.edu.cn.
  • 7 State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic ProductsNational Innovation Platform for Industry-Education Intergration in Vaccine ResearchSchool of Life Sciences, School of Public Health, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, People's Republic of China. yxchen2008@xmu.edu.cn.
  • 8 State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic ProductsNational Innovation Platform for Industry-Education Intergration in Vaccine ResearchSchool of Life Sciences, School of Public Health, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, People's Republic of China. nsxia@xmu.edu.cn.
  • # Contributed equally.
PMID: 37891570 DOI: 10.1186/s13046-023-02848-1
Abstract

Background: Oncolytic viruses are now well recognized as potential immunotherapeutic agents against Cancer. However, the first FDA-approved oncolytic herpes simplex virus 1 (HSV-1), T-VEC, showed limited benefits in some patients in clinical trials. Thus, the identification of novel oncolytic viruses that can strengthen oncolytic virus therapy is warranted. Here, we identified a live-attenuated swine pseudorabies virus (PRV-LAV) as a promising oncolytic agent with broad-spectrum antitumor activity in vitro and in vivo.

Methods: PRV cytotoxicity against tumor cells and normal cells was tested in vitro using a CCK8 cell viability assay. A cell kinase inhibitor library was used to screen for key targets that affect the proliferation of PRV-LAV. The potential therapeutic efficacy of PRV-LAV was tested against syngeneic tumors in immunocompetent mice, and against subcutaneous xenografts of human Cancer cell lines in nude mice. Cytometry by time of flight (CyTOF) and flow cytometry were used to uncover the immunological mechanism of PRV-LAV treatment in regulating the tumor immune microenvironment.

Results: Through various tumor-specific analyses, we show that PRV-LAV infects Cancer cells via the NRP1/EGFR signaling pathway, which is commonly overexpressed in Cancer. Further, we show that PRV-LAV kills Cancer cells by inducing endoplasmic reticulum (ER) stress. Moreover, PRV-LAV is responsible for reprogramming the tumor microenvironment from immunologically naïve ("cold") to inflamed ("hot"), thereby increasing immune cell infiltration and restoring CD8+ T cell function against Cancer. When delivered in combination with immune checkpoint inhibitors (ICIs), the anti-tumor response is augmented, suggestive of synergistic activity.

Conclusions: PRV-LAV can infect Cancer cells via NRP1/EGFR signaling and induce Cancer cells Apoptosis via ER stress. PRV-LAV treatment also restores CD8+ T cell function against Cancer. The combination of PRV-LAV and immune checkpoint inhibitors has a significant synergistic effect. Overall, these findings point to PRV-LAV as a serious potential candidate for the treatment of NRP1/EGFR pathway-associated tumors.

Keywords

Cancer therapy; EGFR; Immune checkpoint; Oncolytic virus; Pseudorabies virus.

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