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. 2015:2:15011.
doi: 10.1038/mto.2015.11. Epub 2015 Jul 22.

Oncolysis by paramyxoviruses: multiple mechanisms contribute to therapeutic efficiency

Olga V Matveeva  1 , Zong S Guo  2 , Svetlana A Shabalina  3 , Peter M Chumakov  4
Affiliations

Oncolysis by paramyxoviruses: multiple mechanisms contribute to therapeutic efficiency

Olga V Matveeva et al. Mol Ther Oncolytics. 2015.

Abstract

Oncolytic paramyxoviruses include some strains of Measles, Mumps, Newcastle disease, and Sendai viruses. All these viruses are well equipped for promoting highly specific and efficient malignant cell death, which can be direct and/or immuno-mediated. A number of proteins that serve as natural receptors for oncolytic paramyxoviruses are frequently overexpressed in malignant cells. Therefore, the preferential interaction of paramyxoviruses with malignant cells rather than with normal cells is promoted. Due to specific genetic defects of cancer cells in the interferon (IFN) and apoptotic pathways, viral replication has the potential to be promoted specifically in tumors. Viral mediation of syncytium formation (a polykaryonic structure) promotes intratumoral paramyxo-virus replication and spreading, without exposure to host neutralizing antibodies. So, two related processes: efficient intratumoral infection spread as well as the consequent mass malignant cell death, both are enhanced. In general, the paramyxoviruses elicit strong anticancer innate and adaptive immune responses by triggering multiple danger signals. The paramyxoviruses are powerful inducers of IFN and other immuno-stimulating cytokines. These viruses efficiently promote anticancer activity of natural killer cells, dendritic cells, and cytotoxic T lymphocytes. Moreover, a neuraminidase (sialidase), a component of the viral envelope of Newcastle Disease, Mumps, and Sendai viruses, can cleave sialic acids on the surface of malignant cells thereby unmasking cancer antigens and exposing them to the immune system. These multiple mechanisms contribute to therapeutic efficacy of oncolytic paramyxovi-ruses and are responsible for encouraging results in preclinical and clinical studies.

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Conflict of interest statement

Olga V. Matveeva is a co-author of a patent entitled “Method for cancer immunotherapy and pharmaceutical compositions based on oncolytic non-pathogenic Sendai virus.”

Figures

Figure 1
Figure 1
Three levels of cancer-specific infection spread for paramyxoviruses. (1) First level of virus specificity for cancer cells is related to overexpression of specific receptors for paramyxoviruses. Sialic acids residues in a form of sialoglycoproteins serve as receptors for NDV, mumps, and SeV. These sialoglycoproteins are frequently overexpressed in malignant cells. CD46 and nectin 4 serve as natural receptors for attenuated strain of MV, and they are also frequently overexpressed in malignant cells. (2) Second level of virus specificity is related to cancer cells’ specific proteases. The replication cycles of paramyxoviruses require protease cleavage of viral glycoproteins for productive cell enter. Desirable proteases for oncolytic viruses that can activate them are expressed preferentially by cancer cells. For example, matrix metalloproteinases are overexpressed in almost all human cancer cells. (3) Third level of virus specificity is related to cancer cells’ specific genetic defects that allow viral replication. During the process of malignization, a cancer cell accumulates many genetic changes. Along with mutations that promote accelerated proliferation and invasion, many cancerous cells are losing abilities to produce interferon (IFN) and to respond to IFN by apoptotic pathway induction. Such abnormalities make these cells highly susceptible to viral infection. So, oncolytic paramyxoviruses due to abundance of cancer-specific receptors and due to cancer-specific genetic defects are more likely spreading among malignant cells rather than among normal cells.
Figure 2
Figure 2
Direct or immuno-mediated cancer cells death. (a) Direct and highly immunogenic cancer cell death through formation of syncytia. Virus-infected cells start expressing viral fusion protein (F) at their cell surface that forces fusion of infected and surrounding noninfected cells and formation of large polykaryonic structures known as syncytia. The syncytia support continuous viral replication and further fusion with new uninfected cells. Eventually, the syncytia die. The syncytia formation allows viral infection to spread even in the presence of high titers of neutralizing antiviral antibodies. This type of cell death assists in viral oncolysis. Proteolytic cleavage of viral protein F0 is needed to activate it and transform it into F1. Only F1 can promote cell fusion into syncytia. For some representatives of paramyxoviruses, F0 that is expressed in infected human cells is fusion incompetent because of the absence of proteolytic cleavage to activate F-protein (F0) and transform it to F1. Therefore, syncytia formation could not expand in tumor tissues, unless they express a protease that could perform appropriate proteolytic cleavage. (b) Immuno-mediated cancer cell death. Paramyxoviruses stimulate innate and adaptive immunity that targets cancer cells. Malignant cells are frequently unable to react to virus infection by producing INF. They are also frequently unable to respond to INF by apoptotic pathway induction. In response to virus infection, normal cells are able to produce INF. Notably, virus induced INF is synthesized by macrophages, dendritic, endothelial and tumor stromal cells. Moreover, in response to virus infection, tumor stromal cells also secrete numerous cytokines that elicit a strong antitumor reaction by attracting macrophages, monocytes, natural killer (NK) cells and other components of the innate immune system. In addition, IFNs and cytokines stimulate dendritic cells (DCs) to educate cytotoxic T-lymphocytes to target tumor cells.
Figure 3
Figure 3
A hypothetical role of viral sialidase in activation of cytotoxic T-lymphocyte response against cancer cells. The removal of sialic acids may unmask hidden tumor antigens and make them more visible by the immune system.
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