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.
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.
J Exp Clin Cancer Res. 2023 Oct 27;42(1):284. doi: 10.1186/s13046-023-02848-1.
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.
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.
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.
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.
溶瘤病毒现已被广泛认为是癌症的潜在免疫治疗药物。然而，首个获得 FDA 批准的溶瘤单纯疱疹病毒 1（HSV-1）T-VEC 在临床试验中对一些患者的疗效有限。因此，有必要寻找能够增强溶瘤病毒治疗效果的新型溶瘤病毒。在这里，我们鉴定出一种活减毒猪伪狂犬病病毒（PRV-LAV），它在体外和体内具有广谱抗肿瘤活性，是一种很有前途的溶瘤剂。
通过 CCK8 细胞活力测定法在体外测试 PRV 对肿瘤细胞和正常细胞的细胞毒性。使用细胞激酶抑制剂文库筛选影响 PRV-LAV 增殖的关键靶点。在免疫功能正常的小鼠中，针对同源肿瘤，以及在裸鼠中针对人癌细胞系的皮下异种移植瘤，测试 PRV-LAV 的潜在治疗效果。使用时间飞行（CyTOF）和流式细胞术来揭示 PRV-LAV 治疗调节肿瘤免疫微环境的免疫学机制。
通过各种肿瘤特异性分析，我们表明 PRV-LAV 通过 NRP1/EGFR 信号通路感染癌细胞，该信号通路在癌症中普遍过表达。此外，我们表明 PRV-LAV 通过诱导内质网（ER）应激杀死癌细胞。此外，PRV-LAV 负责将肿瘤微环境从免疫原性幼稚（“冷”）重塑为炎症（“热”），从而增加免疫细胞浸润并恢复 CD8 T 细胞对癌症的功能。当与免疫检查点抑制剂（ICIs）联合使用时，抗肿瘤反应增强，提示协同作用。
PRV-LAV 可以通过 NRP1/EGFR 信号感染癌细胞，并通过 ER 应激诱导癌细胞凋亡。PRV-LAV 治疗还恢复了 CD8 T 细胞对癌症的功能。PRV-LAV 与免疫检查点抑制剂的联合使用具有显著的协同作用。总的来说，这些发现表明 PRV-LAV 是治疗 NRP1/EGFR 通路相关肿瘤的一个有前途的候选药物。
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