Immunotherapy against cancer-related viruses - PubMed (original) (raw)

Review

Haruko Tashiro et al. Cell Res. 2017 Jan.

Abstract

Approximately 12% of all cancers worldwide are associated with viral infections. To date, eight viruses have been shown to contribute to the development of human cancers, including Epstein-Barr virus (EBV), Hepatitis B and C viruses, and Human papilloma virus, among others. These DNA and RNA viruses produce oncogenic effects through distinct mechanisms. First, viruses may induce sustained disorders of host cell growth and survival through the genes they express, or may induce DNA damage response in host cells, which in turn increases host genome instability. Second, they may induce chronic inflammation and secondary tissue damage favoring the development of oncogenic processes in host cells. Viruses like HIV can create a more permissive environment for cancer development through immune inhibition, but we will focus on the previous two mechanisms in this review. Unlike traditional cancer therapies that cannot distinguish infected cells from non-infected cells, immunotherapies are uniquely equipped to target virus-associated malignancies. The targeting and functioning mechanisms associated with the immune response can be exploited to prevent viral infections by vaccination, and can also be used to treat infection before cancer establishment. Successes in using the immune system to eradicate established malignancy by selective recognition of virus-associated tumor cells are currently being reported. For example, numerous clinical trials of adoptive transfer of ex vivo generated virus-specific T cells have shown benefit even for established tumors in patients with EBV-associated malignancies. Additional studies in other virus-associated tumors have also been initiated and in this review we describe the current status of immunotherapy for virus-associated malignancies and discuss future prospects.

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Figures

Figure 1

Figure 1

The model of EBV life cycle and latency states. EBV primary infection occurs in the oropharyngeal cavity. EBV infects naive B cells and expresses its entire latency genes (Latency 3, growth program). Although Latency 3 drives B cell transformation and proliferation, these cells are highly immunogenic, and thus EB-VSTs eliminate these Latency 3 cells in immunocompetent hosts. The infected B cells downregulate the expression of its immunogenic proteins, allowing viral persistence (Latency 2, default program). Then these cells migrate to the peripheral blood where they express EBNA1 (Latency 1, EBNA1 only program) or no viral proteins at all (Latency 0, Latency program). These memory compartments are not detected by the immune system and are likely the sites of long-term persistence. The latently infected memory B cells undergo terminal differentiation into plasma cells which can produce viruses (Lytic program). Viruses released from plasma cells can infect epithelial cells where they are amplified before shedding.

Figure 2

Figure 2

Manufacturing of EB-VSTs. (A) IFN-γ selection: stimulate PBMCs with EBV peptides and capture IFN-γ-secreting cells with magnetic beads. (B) Streptamer magnetic beads selection: select EB-VSTs using HLA-peptide streptamer and isolate them with magnetic beads. (C) Pepmix stimulation method: stimulate PBMCs with EBV peptides and expand them in the presence of cytokines.

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