Arming beneficial viruses to treat pancreatic cancer

• Published in: Canadian Journal of Surgery 2022-11, Vol.65, p.S108-S108
• Main Authors: Mansouri, Sarah, Léveillé, Maxime, Lawson, Christine, Collin, Yves, Tai, Lee-Hwa
• Format: Article
• Language: English
• Subjects: Apoptosis; Immune system; Infections; Laboratories; Light; Pancreatic cancer; Tumors; Viral infections; Viruses
• ISSN: 0008-428X; 1488-2310

Background: Oncolytic virotherapy is a promising treatment option for immunologically cold tumours, such as pancreatic ductal adenocarcinoma (PDAC). Immunologically cold tumours are tumours with low rates of tumour infiltrating lymphocytes, allowing them to evade the immune system. Immune checkpoint inhibitors have failed to show clinical efficacy in this disease owing to the relative absence of immune cells in the PDAC tumour microenvironment. Vesicular stomatitis virus (VSV), an oncolytic virus with a long-established safety profile, specifically infects, replicates and lyses cancer cells, without harming healthy cells. Furthermore, infection with VSV stimulates the innate and adaptive immune system to mount a strong anti-tumour immune response toward cancer cells. This host anti-tumour immunity is aimed at both local and distant disease and is mediated by immune-activating proteins released upon immunogenic cell death (ICD) of the cancer cells induced by viral infection. We hypothesized that arming oncolytic VSV with an immune-stimulating transgene (TNFSF14, otherwise known as LIGHT) will generate a significant antitumour immune response in PDAC, leading to durable tumour regression. The first objective of this study was to characterize the fitness of the newly engineered VSV-LIGHT, including its capacity to infect, replicate, induce cell death and produce bioactive LIGHT in PDAC cell lines. The second objective was to assess the ability of VSV-LIGHT to induce immunogenic cell death following lysis of pancreatic cancer cell lines. The third objective will be to test the tumour targeting ability of VSV-LIGHT in vivo. Methods: The oncolytic virus VSV-LIGHT, engineered in our laboratory, was used in this study, and compared with its parental VSV strain. The murine PDAC cell lines Panc02 and MiaPaca1 were used for in vitro experiments. Multiple assays were performed to investigate the research hypothesis, including cytotoxicity, viral replication, and protein production (Western blot, flow cytometry). Results: Our results demonstrated that VSV-LIGHT retains its abilities to infect, replicate and lyse PDAC cell lines despite the insertion of the LIGHT transgene. In addition, we measured bioactive LIGHT following infection. Furthermore, we detected biomarkers of ICD including ATP and HMGB1 following infection with VSV-LIGHT. Conclusion: These results suggest that VSV-LIGHT is a functional virotherapeutic and possesses an immune activating capacity. Taken toge