Activation and Subversion of MDA5-Dependent Immune Responses by the Engineered Oncolytic Poliovirus PVSRIPO

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2018

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Abstract

Cancer-specific cytopathogenicity of oncolytic viruses is often defined by viral

sensitivity to innate antiviral immune responses, e.g. type I Interferons (IFNs), limiting

cytotoxicity to cells lacking these responses. However, recent work suggests some cancer

cells inhibit IFN-sensitive oncolytic viruses, preventing efficacy. IFNs are also antiproliferative in cancer and activate anti-tumor immunity.

In this work I show that the recombinant poliovirus PVSRIPO, currently in

clinical trial as a treatment for glioblastoma, induces and evades IFN-β signaling in

cancer cell lines infected at low doses. Likewise, IFN-α treatment of cancer cells

inhibited PVSRIPO less than on the related encephalomyocarditis virus (EMCV).

Antibody blockade of the IFN-α/β receptor had no effect on either virus in IFN-secreting

melanoma cell lines. Depletion of the pattern recognition receptor MDA5 or inhibition of

TBK1/IKKε eliminated IFN responses to PVSRIPO or EMCV and promoted EMCV, but

not PVSRIPO, replication. The Toll-like receptor 3 (TLR3) agonist poly(I:C) suppressed

EMCV (semi-independently of type I IFN signaling) but not PVSRIPO. Thus, MDA5 and

TLR3 provoke type I IFN-dependent and -independent antiviral effects, likely involving

upregulation of genes downstream of TBK1/IKKε. PVSRIPO subverts anti-viral

immunity in cancer cells at low doses and activates type I IFNs through MDA5,

supporting its oncolytic and immunotherapeutic use even in IFN-competent cancers.

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Walton, Ross William (2018). Activation and Subversion of MDA5-Dependent Immune Responses by the Engineered Oncolytic Poliovirus PVSRIPO. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/18234.

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