Mechanistic insights into the oncolytic activity of vesicular stomatitis virus in cancer immunotherapy

Oncolytic Virotherapy, Oct 2015

Mechanistic insights into the oncolytic activity of vesicular stomatitis virus in cancer immunotherapy Boris Simovic, Scott R Walsh, Yonghong Wan Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada Abstract: Immunotherapy and oncolytic virotherapy have both shown anticancer efficacy in the clinic as monotherapies but the greatest promise lies in therapies that combine these approaches. Vesicular stomatitis virus is a prominent oncolytic virus with several features that promise synergy between oncolytic virotherapy and immunotherapy. This review will address the cytotoxicity of vesicular stomatitis virus in transformed cells and what this means for antitumor immunity and the virus' immunogenicity, as well as how it facilitates the breaking of tolerance within the tumor, and finally, we will outline how these features can be incorporated into the rational design of new treatment strategies in combination with immunotherapy. Keywords: virotherapy, rhabdovirus, anti-tumor immunity, t cell, natural killer cell, therapeutic vaccine

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Mechanistic insights into the oncolytic activity of vesicular stomatitis virus in cancer immunotherapy

Oncolytic Virotherapy Mechanistic insights into the oncolytic activity of vesicular stomatitis virus in cancer immunotherapy Boris Simovic Scott R w alsh Yonghong w an 0 0 Department of Pathology and Molecular Medicine, McMaster immunology Research Centre, Faculty of Health Sciences, McMaster University , Hamilton, ON , Canada Immunotherapy and oncolytic virotherapy have both shown anticancer efficacy in the clinic as monotherapies but the greatest promise lies in therapies that combine these approaches. Vesicular stomatitis virus is a prominent oncolytic virus with several features that promise synergy between oncolytic virotherapy and immunotherapy. This review will address the cytotoxicity of vesicular stomatitis virus in transformed cells and what this means for antitumor immunity and the virus' immunogenicity, as well as how it facilitates the breaking of tolerance within the tumor, and finally, we will outline how these features can be incorporated into the rational design of new treatment strategies in combination with immunotherapy. - 8 1 0 2 l u J 2 1 n o 3 7 . 7 1 1 . 7 3 . 4 5 y b / m o c . rvssoepe l.syeon .d lu structure and organization of the viral genome, the relative abundance of transcripts/protein products and their functions, and the structure of the mature virion. A number of factors, such as its short replication time, the large amount of progeny generated by a single cycle of infection, a lack of preexisting humoral immunity in the general population, its broad tissue tropism, and its amenability to genetic engineering, make VSV an excellent OV. What is especially appealing about the use of VSV is its large safety window owing to its inability to induce transformation in healthy cells, as well as its sensitivity to type I interferons (IFNs).6 VSV attachment and entry True to its originally intended purpose, the first useful feature of VSV for combination with immunotherapy is its ability to directly facilitate tumor debulking. The viral glycoprotein (G protein) is embedded in the viral envelope and facilitates attachment and entry into the host cell by binding to the low-density-lipoprotein receptor (LDLR) and its family members.7 Members of the LDLR family are ubiquitously expressed by mammalian cells; this allows VSV to infect virtually any cell type. Therefore, application of VSV in oncolytic virotherapy is not restricted by host 158 receptor expression and can be used in an array of tumor types. In addition, this means that VSV entry is not restricted to cancer cells. However, VSV replication is still a desirable feature of the virus due to its extreme sensitivity to type I IFN (discussed in the section “Tumor-specific replication of VSV and type I IFN”). Tumor-specific replication of VSV and type I IFN Activation of innate immune mechanisms by type I IFN protects normal cells from VSV infection-induced lysis, while cancer cells, which commonly have defects in the type I IFN signaling pathway, are unable to induce a protective innate immune response. VSV is a potent inducer of type I IFNs and the rapid systemic dissemination of type I IFN after VSV infection selectively shields normal cells from VSV infection, thus restricting infection to cancer cells. VSV has mechanisms to inhibit type I IFN signaling, but these mechanisms are reliant on expression of the M protein to induce shutdown of gene expression within infected cells.8–10 VSV-M protein is able to block the nuclear export of host mRNA. This is achieved when M protein associates with nuclear pore complexes (NPCs) embedded in the nuclear envelope via nucleoporin Nup98 and the mRNA export factor Rae1 (Figure 2). The association of M protein to NPCs via Nup98 is mediated by amino acid residues 51–59 of the M protein, and it results in the blockade of nuclear export of mRNAs into the cytosol of the infected cell.9,11 Additionally, the M protein Cytoplasm Ribosome elF4F complex Nuclear pore complex Nup98/Rae1 heterodimer VSV M protein Host mRNA TFIID TBP RNAP II Host promoter Nucleoplasm 8 1 0 2 l u J 2 1 n o 3 7 . 7 1 1 . 7 3 . 4 5 y b / m o c . rvssoepe l.syeon can inactivate DNA-dependent RNA polymerase II and stop the transcription of host antiviral response genes (Figure 2). This is accomplished via host factor-mediated inactivation of the TATA-binding protein subunit of the transcription factor IID (TFIID).8,12,13 Finally, the M protein is capable of dephosphorylating eIF4E and 4E-binding protein 1, thereby altering the structure of the eIF4F cap-binding complex, which results in inhibition of the translation of host mRNA while allowing for the translation of viral mRNA (Figure 2).10 The global suppression of host gene expression by VSV-M favors viral protein synthesis but also blunts infected cells’ ability to produce type I IFN and respond to exogenous type I IFN. This is believed to be the main mechanism for VSV’s oncolytic activity because the shutdown of host gene expression induces a cellular stress re (...truncated)


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Boris Simovic, Scott R Walsh, Yonghong Wan. Mechanistic insights into the oncolytic activity of vesicular stomatitis virus in cancer immunotherapy, Oncolytic Virotherapy, 2015, pp. 157-167, DOI: 10.2147/OV.S66079