Cancer is an increasingly severe global public health issue, with an urgent need for new anticancer drugs. Recent studies have identified oncolytic viruses as a relatively new class of cancer immunotherapy. Oncolytic viruses preferentially infect and kill cancer cells over normal cells, an effect largely attributed to the significant genetic differences between cancerous and normal cells. Additionally, oncolytic viruses can kill malignant cells by inducing an inflammatory microenvironment and modulating the tumor vascular system. Given these characteristics, oncolytic viruses have become very promising anticancer agents.
Researchers from Xiamen University recently published an article in the J Exp Clin Cancer Res journal titled “The potential of swine pseudorabies virus attenuated vaccine for oncolytic therapy against malignant tumors.” This study shows that the attenuated swine pseudorabies virus (PRV-LAV) can infect cancer cells via the NRP1/EGFR signaling pathway and induce cancer cell apoptosis through endoplasmic reticulum stress. PRV-LAV treatment also restores the function of CD8+ T cells against cancer.
However, the first oncolytic herpes simplex virus 1 (HSV-1) T-VEC approved by the FDA showed limited efficacy in some patient clinical trials. Therefore, identifying new oncolytic viruses that can enhance oncolytic virus therapy is necessary. Here, the researchers identified PRV-LAV as a promising oncolytic agent with broad-spectrum antitumor activity in vitro and in vivo.
The researchers used the CCK8 cell viability assay to detect PRV’s cytotoxicity towards tumor cells and normal cells in vitro. A kinase inhibitor library was utilized to screen for key targets affecting PRV-LAV proliferation. The potential therapeutic effect of PRV-LAV on syngeneic tumors in immunocompetent mice and on human cancer cell line subcutaneous xenografts in nude mice was tested. CyTOF and flow cytometry were used to reveal the immunological mechanisms by which PRV-LAV treatment modulates the tumor immune microenvironment.
Through various tumor-specific analyses, the researchers discovered that PRV-LAV infects cancer cells via the NRP1/EGFR signaling pathway, which is often overexpressed in cancer. Moreover, they found that PRV-LAV kills cancer cells by inducing endoplasmic reticulum (ER) stress. Furthermore, PRV-LAV is responsible for reprogramming the tumor microenvironment from immunologically naive (“cold”) to inflammatory (“hot”), thereby increasing immune cell infiltration and restoring the anticancer function of CD8+ T cells. When used in combination with immune checkpoint inhibitors (ICIs), the antitumor response was enhanced, indicating a synergistic effect.
In summary, the study established an effective strategy for screening oncolytic viruses from attenuated live vaccines and confirmed PRV-LAV’s oncogenicity related to the NRP1/EGFR signaling pathway. It also confirmed that PRV-LAV could selectively induce cancer cell death through the apoptosis signaling pathway of endoplasmic reticulum stress. Overall, the study highlighted the efficacy of personalized treatment of malignant tumors through NRP1/EGFR signaling. It is foreseeable that oncolytic PRV-LAV will become an important tool in the arsenal for treating human tumors.
Reference
1. Wang, Guosong, et al. “The potential of swine pseudorabies virus attenuated vaccine for oncolytic therapy against malignant tumors.” Journal of Experimental & Clinical Cancer Research 42.1 (2023): 284.