Down‐regulation of type I interferon receptor sensitizes bladder cancer cells to vesicular stomatitis virus‐induced cell death

Abstract

The intrinsic oncolytic specificity of vesicular stomatitis virus (VSV) is currently being exploited to develop alternative therapeutic strategies for bladder cancer and other cancers. Previously we reported that oncolytic VSV is a potent agent for intravesical treatment of high risk bladder cancer. We observed that VSV preferentially targeted bladder cancer cells resistant to type I interferon (IFN) treatment. The goal of the current study was to further elucidate the nature of the molecular defect of IFN signaling by which bladder cancer cells become susceptible to VSV infection. Using a tissue microarray composed of human bladder cancer cores, we observed that expression of type I IFN receptor (IFNAR) was decreased relative to normal bladder tissue. Advanced bladder cancers had even lower expression of IFNAR. We found that bladder cancer cells susceptible to VSVinduced lysis had low expression of IFNAR as well. We hypothesized that down-regulation of IFNAR in bladder cancer cells may be a molecular mechanism responsible for resistance to type I IFN treatment and sensitivity to VSV oncolysis. SiRNA knockdown of IFNAR indeed facilitated replication of VSV in cells previously resistant to VSV treatment. Blocking IFNAR with a neutralizing antibody showed a similar effect. Hence down-regulation of IFNAR in bladder cancer may be one of the primary molecular mechanisms for clinical IFN resistance. However, this also facilitates VSV replication and oncolysis in high risk bladder cancers and provides a basis for selecting bladder cancer patients for IFN or oncolytic VSV therapy in future clinical trials.Bladder cancer is the second most common cancer of the urinary tract, and overall ranks among the top 10 cancers in men and women. 1-3 Transitional cell carcinoma (TCC), the most common type of bladder cancer, is associated with both high recurrence and progression rates. Despite initial success with intravesical bacillus Calmette-Guérin (BCG) immunotherapy, up to 80% of patients with high-risk superficial disease develop recurrent tumors, of which 20-30% evolve into more aggressive, potentially lethal cancers. 4 Although intravesical combination therapy of BCG and IFN-a demonstrated superiority over BCG alone, 5 as tumors progress they may acquire molecular defects in their ability to respond to IFN; 6 thus, the effects of combined IFN and BCG treatment may be compromised.VSV is an enveloped, negative-sense RNA virus that selectively replicates in IFN pathway defective cells, but is strongly suppressed in IFN-responsive normal tissues. 7 Indeed, we have previously shown that oncolytic VSV preferentially targeted bladder cancer cells resistant to type I interferon (IFN) treatment and that these viruses are potent agents for intravesical treatment of high risk bladder cancer. 8 VSV may potentially be used to treat bladder cancers refractory to BCG and IFN, if the nature of the impairment in IFN signaling in aggressive bladder cancer is elucidated.In this study, we assessed IFN signaling pathways in bladder cancer cells ...

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