Overcoming cancer cell resistance to VSV oncolysis with JAK1/2 inhibitors

Area of Science:

• Oncolytic virotherapy
• Cancer biology
• Immunology

Background:

• Oncolytic viruses like vesicular stomatitis virus (VSV) show promise against cancer.
• However, cancer cells can develop resistance to VSV, often mediated by type I interferon (IFN) responses.
• Identifying strategies to overcome this resistance is crucial for effective virotherapy.

Purpose of the Study:

• To investigate the efficacy of Janus kinase (JAK) 1/2 inhibitors in overcoming VSV resistance in human head and neck cancer cells.
• To explore the underlying mechanisms of JAK inhibitor-mediated sensitization to VSV.
• To evaluate the potential of combining JAK inhibitors with VSV for cancer treatment.

Main Methods:

• VSV oncolysis was assessed in a panel of head and neck cancer cell lines.
• Cells were pre-treated with JAK1/2 inhibitors (JAK inhibitor I, ruxolitinib) or other kinase inhibitors before VSV infection.
• Gene expression analysis was performed to evaluate antiviral gene induction and the effect of JAK inhibitors on these pathways.

Main Results:

• VSV resistance in SCC25 and SCC15 cells was reversed by JAK1/2 inhibitors, leading to a 100- to 1000-fold increase in viral infection, spread, and progeny yield.
• JAK inhibitors reduced the constitutive expression of IFN-α/β responsive antiviral genes in resistant cells, enhancing VSV replication.
• Short pre-treatment (1 hour) with JAK inhibitors was sufficient to reverse resistance, even when virus was added 24 hours later.
• Inhibitors targeting HDAC, PI3K, mTOR, or STAT3 pathways were ineffective.

Conclusions:

• JAK1/2 inhibitors effectively reverse VSV resistance in head and neck cancer cells.
• This sensitization is mediated by suppressing antiviral gene expression.
• Combining JAK inhibitors with VSV represents a promising strategy for enhancing oncolytic virotherapy efficacy.