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Updated: Dec 11, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
[The State of The Jak/Stat Pathway Affects the Sensitivity of TumorCells to Oncolytic Enteroviruses]
T H Le1,2, A V Lipatova1, M A Volskaya1
1Engelhardt Institute of Molecular Biology Russian Academy of Sciences, Moscow, 119991 Russia.
Abstract:
A test of the sensitivity of seven colon cancer cell lines to a panel of 12 nonpathogenic human enteroviruses revealed significant differences in the ability of tumor cells to become infected and replicate different viral strains. Among the factors that can affect the sensitivity of cells to viruses are differences in the state of the mechanisms of antiviral protection, associated with a reaction to type I interferons. Using the two colon cancer cell lines CaCo2 and LIM1215 as a model, significant differences were revealed in the ability of cells to defend themselves against virus infection after 16 hours of treatment with 1000 units/mL of interferon-alpha. To study the effect of the state of the interferon response system, represented by the Jak/STAT signaling pathway, on the sensitivity of cells to different strains of enteroviruses, HEK293T cell lines were used. These are capable of supporting replication of each of the tested enteroviruses, as well as maintaining the ability to protect against viral infection after the treatment with interferon. Using the CRISPR/Cas9 system, HEK293T sublines with knockouts of the IFNAR1 and STAT2 genes were obtained. The sensitivity of control and knockout cells to infection with five strains of enteroviruses and the vesicular stomatitis virus was analyzed. It was noted that knockout of the IFNAR1 and STAT2 genes resulted in an increased sensitivity to all tested viruses. In knockout cells, the levels of reproduction of the vaccine derived of poliovirus type 1, Echoviruses 7 and 30, and Coxsackie viruses B5 and A7 were also significantly increased in comparison with the control HEK293T cells. Thus, deficiencies in the Jak/STAT signaling pathway in tumor cells lead to an overall increase in the sensitivity to oncolytic viruses.
Insights
Tumor cells show varied sensitivity to enteroviruses, influenced by antiviral defenses. Disrupting the Jak/STAT pathway, crucial for interferon response, significantly increases cancer cell susceptibility to oncolytic viruses.
Area of Science:
- Virology
- Immunology
- Oncology
Background:
- Cancer cells exhibit differential susceptibility to viral infections.
- Antiviral defense mechanisms, particularly type I interferon responses, play a role in cellular resistance to viruses.
- The Jak/STAT signaling pathway is central to the cellular response to interferons.
Purpose of the Study:
- To investigate the impact of interferon response pathway integrity on the sensitivity of colon cancer cells to enteroviruses.
- To elucidate the role of the Jak/STAT signaling pathway in antiviral defense against oncolytic viruses.
Main Methods:
- Differential sensitivity of seven colon cancer cell lines to 12 enterovirus strains was assessed.
- Interferon-alpha treatment effects on CaCo2 and LIM1215 cell line antiviral defense were evaluated.
- CRISPR/Cas9 gene editing was used to create IFNAR1 and STAT2 knockout HEK293T cell lines to study Jak/STAT pathway function.
- Sensitivity of control and knockout cells to various enteroviruses and vesicular stomatitis virus was analyzed.
Main Results:
- Significant variations in enterovirus infection and replication were observed across different colon cancer cell lines.
- Interferon-alpha treatment modulated the antiviral defense capabilities of colon cancer cells.
- Knockout of IFNAR1 and STAT2 genes in HEK293T cells led to a marked increase in sensitivity to all tested viruses, including poliovirus, echoviruses, and coxsackieviruses.
- Replication levels of multiple enterovirus strains were significantly higher in knockout cells compared to controls.
Conclusions:
- Deficiencies in the Jak/STAT signaling pathway compromise the antiviral defense of tumor cells.
- Impaired interferon response mechanisms enhance tumor cell susceptibility to oncolytic viruses.
- Targeting the Jak/STAT pathway could be a strategy to improve oncolytic virotherapy efficacy.
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