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<p>Tumors and cancer cell lines exhibit varying levels of activation in interferon (IFN) pathways and expression of IFN-stimulated genes (ISGs). This heterogeneity correlates with differential susceptibility to oncolytic viruses (OVs), which exploit impaired IFN responses to replicate in and kill malignant cells preferentially. A current challenge in oncolytic virotherapy (OVT) is to develop strategies that selectively inhibit IFN responses in malignant cells, thereby expanding the therapeutic range of OVs. This study proposes leveraging the vulnerability of tumor cells to BH3 mimetic compounds and caspase-mediated inhibition of IFN responses to enhance OVT in OV-resistant tumors. Analysis of the bladder cancer (BC) cohort from The Cancer Genome Atlas (TCGA) revealed a cluster of antiviral ISGs exhibiting positively correlated expression, and subpopulations of high- and low ISG expressors. A similar pattern was observed in the urinary tract cohort of the Cancer Cell Line Encyclopedia (CCLE), suggesting that this ISG expression profile is regulated in a cell-autonomous manner. We study two BC cell lines, T24 and UMUC3, differing in ISG expression, and SKMEL3 melanoma cells, a non-BC cell line with features similar to T24. T24 and SKMEL3 cells exhibited Janus kinase (JAK)-dependent resistance to the oncolytic orbivirus Epizootic Hemorrhagic Disease Virus Tel Aviv University (EHDV-TAU). Treatment with the BH3 mimetic Abt737 activated caspases, suppressed IFN-mediated antiviral responses, and enabled productive EHDV-TAU infection in tumor cells but not in normal fibroblasts. Mechanistically, Abt737 induced caspase-dependent cleavage of signal transduction Signal Transducer and Activator of Transcription 1 (STAT1) in both cell lines and interferon regulatory factor 3 (IRF3) in T24 cells, suggesting disruption of IFN/JAK/STAT signaling and IFN induction. In these cells, the EHDV-TAU + Abt737 combination increased the plasma membrane exposure of calreticulin and extracellular ATP, markers of immunogenic cell death. In contrast, combining Abt737 with a mutant vesicular stomatitis virus (VSVΔ51M) reduced viral titers, indicating virus-specific effects. This strategy appears optimal for OVs like EHDV-TAU, which thrive in apoptotic environments. Overall, this approach may broaden OVT’s therapeutic reach by leveraging apoptosis to overcome tumor antiviral resistance.</p>

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Induction of caspase-mediated suppression of interferon signaling potentiates viral oncolysis of resistant tumor cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月24日

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  • Vladimir Bozhdansky,
  • Shelly Tayar,
  • Shlomi Kashkash,
  • Eran Bacharach,
  • Marcelo Ehrlich

摘要

Tumors and cancer cell lines exhibit varying levels of activation in interferon (IFN) pathways and expression of IFN-stimulated genes (ISGs). This heterogeneity correlates with differential susceptibility to oncolytic viruses (OVs), which exploit impaired IFN responses to replicate in and kill malignant cells preferentially. A current challenge in oncolytic virotherapy (OVT) is to develop strategies that selectively inhibit IFN responses in malignant cells, thereby expanding the therapeutic range of OVs. This study proposes leveraging the vulnerability of tumor cells to BH3 mimetic compounds and caspase-mediated inhibition of IFN responses to enhance OVT in OV-resistant tumors. Analysis of the bladder cancer (BC) cohort from The Cancer Genome Atlas (TCGA) revealed a cluster of antiviral ISGs exhibiting positively correlated expression, and subpopulations of high- and low ISG expressors. A similar pattern was observed in the urinary tract cohort of the Cancer Cell Line Encyclopedia (CCLE), suggesting that this ISG expression profile is regulated in a cell-autonomous manner. We study two BC cell lines, T24 and UMUC3, differing in ISG expression, and SKMEL3 melanoma cells, a non-BC cell line with features similar to T24. T24 and SKMEL3 cells exhibited Janus kinase (JAK)-dependent resistance to the oncolytic orbivirus Epizootic Hemorrhagic Disease Virus Tel Aviv University (EHDV-TAU). Treatment with the BH3 mimetic Abt737 activated caspases, suppressed IFN-mediated antiviral responses, and enabled productive EHDV-TAU infection in tumor cells but not in normal fibroblasts. Mechanistically, Abt737 induced caspase-dependent cleavage of signal transduction Signal Transducer and Activator of Transcription 1 (STAT1) in both cell lines and interferon regulatory factor 3 (IRF3) in T24 cells, suggesting disruption of IFN/JAK/STAT signaling and IFN induction. In these cells, the EHDV-TAU + Abt737 combination increased the plasma membrane exposure of calreticulin and extracellular ATP, markers of immunogenic cell death. In contrast, combining Abt737 with a mutant vesicular stomatitis virus (VSVΔ51M) reduced viral titers, indicating virus-specific effects. This strategy appears optimal for OVs like EHDV-TAU, which thrive in apoptotic environments. Overall, this approach may broaden OVT’s therapeutic reach by leveraging apoptosis to overcome tumor antiviral resistance.