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.
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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
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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
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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)