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Review
, 28 (6), e2008

Defects in Interferon Pathways as Potential Biomarkers of Sensitivity to Oncolytic Viruses

Affiliations
Review

Defects in Interferon Pathways as Potential Biomarkers of Sensitivity to Oncolytic Viruses

Olga V Matveeva et al. Rev Med Virol.

Abstract

Increased sensitivity of cancer cells to viruses is a prerequisite for the success of oncolytic virotherapy. One of the major causes of such a phenotype is the disruption of innate antiviral defenses associated with dysfunction of type 1 interferons (IFNs) that permits unlimited replication of viruses in cancer cells. Defects in IFN pathways help cancer progression by providing additional advantages to tumor cells. However, while these defects promote the survival and accelerated proliferation of malignant cells, they facilitate viral replication and thus enhance the efficiency of viral oncolysis. This review describes a broad spectrum of defects in genes that participate in IFN induction and IFN response pathways. Expression levels and/or functional activities of these genes are frequently low or absent in cancer cells, making them sensitive to virus infection. Therefore, certain specific defects in IFN signaling cascades might serve as potential biomarkers to help in identifying individual cancer patients who are likely to benefit from oncolytic virotherapy.

Keywords: IFN defects in cancer cell; biomarkers; defects in IFN induction; defects in IFN pathways; defects in IFN response; malfunction of IFN signaling cascade; oncolytic virotherapy; oncolytic viruses; viral oncolysis.

Conflict of interest statement

The authors declare that there is no conflict of interest regarding the publication of this article.

Figures

Figure 1
Figure 1
Toll‐like receptors (TLRs) and their downstream signaling. Toll‐like receptors are membrane attached pattern recognition receptors (PRRs) that initiate pathways that produce IFN and proinflammatory cytokines. TLR 2 and TLR9 are activated by viral DNA, TLR3 by viral double stranded RNA, and TLR7/8 by single‐stranded RNA. Toll‐like receptor 2 is located on the outer membrane of the cell, while TLR 3, TLR7/8, and TLR9 are associated with an endosome membrane. After activation by viral nucleic acids, TLRs engage adapter proteins and activate them. The complexes of TLRs with activated adaptor proteins phosphorylate interferon regulatory factors 3 and/or 7 (IRF3 and/or IRF7). Phosphorylated IRF3 and IRF7 relocate from the cytoplasm to the nucleus, where they trigger type 1 IFN production. Through an alternative pathway, the TLR/adaptor protein complexes trigger proinflammatory cytokine production. Malfunction of TLR receptors or IRFs disrupts downstream pathways, making cancer cells vulnerable to oncolytic virus infection
Figure 2
Figure 2
Interferon (IFN) signal amplification loop. RIG‐I, MDA5, and PKR are functionally activated by viral RNAs. After activation, they trigger signaling cascades that result in increased production and secretion of type 1 IFNs. In turn, secreted IFN‐beta interacts with intramembrane receptors of the cell in which it was produced or of another cell. Such interaction initiates autocrine or paracrine downstream signaling pathways, resulting in increased binding of IRF1 to promoters of RIG‐I, MDA5, and PKR. Such binding stimulates transcription of these genes and ultimately increases production of the relevant proteins
Figure 3
Figure 3
cGAS viral DNA sensor and its downstream signaling. GMP‐AMP synthase (cGAS) is a cytosolic sensor of viral DNA that, after activation by foreign DNA, triggers a type 1 IFN response. cGAS forms a complex with adaptor protein STING, which promotes phosphorylation of interferon regulatory factors 3 and/or 7 (IRF3 and/or IRF7). Phosphorylated IRF3 and IRF7 relocate from the cytoplasm to the nucleus, where they trigger type 1 IFN production. Malfunction of cGAS, STING, IRF3, or IRF7 disrupts downstream IFN production pathways, making cancer cells vulnerable to oncolytic virus infection
Figure 4
Figure 4
Viral RNA sensing proteins and their downstream signaling. Viral RNA activates the protein product of the OAS3 gene, which in turn activates RNase L that cleaves cytosolic viral RNA. RNA digestion products activate protein kinase PKR and the 2 helicases RIG1 and MDA5. After activation, PKR undergoes autophosphorylation and phosphorylates the translation initiation factor eIF2α. The phosphorylation of the initiation factor leads to translational arrests of both cellular and viral mRNAs, and these arrests promote apoptosis. Protein kinase R, RIG1, and MDA5 also participate in a signal transduction pathway that triggers IFN‐beta transcription and limits viral spread. Protein kinase R, RIG1, and MDA5 form complexes with adaptor proteins that trigger phosphorylation of interferon regulatory factors 3 and/or 7 (IRF3 and/or IRF7). After phosphorylation, IRF3 and IRF7 relocate from the cytoplasm to the nucleus, where they trigger type 1 IFN transcription. Malfunction of OAS3, RNase L, PKR, RIG‐I, MDA5, IRF3, or IRF7 disrupts downstream IFN induction pathways, making cancer cells vulnerable to oncolytic virus infection
Figure 5
Figure 5
IFN‐alpha and IFN‐beta response pathways. Type 1 IFN response is triggered by a cell surface receptor represented by a complex of 2 transmembrane subunits IFNAR1 and IFNAR2. After interaction with IFN‐alpha or IFN‐beta, the complex activates receptor‐associated Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK 2). The kinases phosphorylate the signal transducer and activator of transcription 1 (STAT1) and STAT2 proteins. These phosphorylated proteins (STAT1 and STAT2), in the form of a dimer, interact with IFN‐regulatory factor 9 (IRF9, also known as p48) and form a trimolecular complex called IFN‐stimulated gene factor 3. Interferon‐stimulated gene factor 3 relocates from the cytoplasm to the nucleus, where it activates transcription of interferon stimulated genes. Interferon stimulated genes encode a family of proteins that inhibit multiple stages of viral infection, including virus entry, translation, replication, assembly, and spread. Malfunction of IFNAR1, IFNAR2, JAK1, STAT1, STAT2, and/or IRF9 disrupts transcription of IFN‐stimulated genes, making cancer cells vulnerable to oncolytic virus infection
Figure 6
Figure 6
Host requirements for viral infection of tumor cells. For productive infection, viruses require cell to express virus receptors and to have a malfunctioning IFN pathway. Some virus families also require cells to express processing enzymes, without which infective virions cannot be formed

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