Abstract
Simple SummaryThe Epstein–Barr virus, also termed human herpes virus 4, is a human pathogenic double-stranded DNA virus. It is highly prevalent and has been linked to the development of 1–2% of cancers worldwide. EBV-associated malignancies encompass various structural and epigenetic alterations. In addition, EBV-encoded gene products and microRNAs interfere with innate and adaptive immunity and modulate the tumor microenvironment. This review provides an overview of the characteristic features of EBV with a focus on the intrinsic and extrinsic immune evasion strategies, which contribute to EBV-associated malignancies.The detailed mechanisms of Epstein–Barr virus (EBV) infection in the initiation and progression of EBV-associated malignancies are not yet completely understood. During the last years, new insights into the mechanisms of malignant transformation of EBV-infected cells including somatic mutations and epigenetic modifications, their impact on the microenvironment and resulting unique immune signatures related to immune system functional status and immune escape strategies have been reported. In this context, there exists increasing evidence that EBV-infected tumor cells can influence the tumor microenvironment to their own benefit by establishing an immune-suppressive surrounding. The identified mechanisms include EBV gene integration and latent expression of EBV-infection-triggered cytokines by tumor and/or bystander cells, e.g., cancer-associated fibroblasts with effects on the composition and spatial distribution of the immune cell subpopulations next to the infected cells, stroma constituents and extracellular vesicles. This review summarizes (i) the typical stages of the viral life cycle and EBV-associated transformation, (ii) strategies to detect EBV genome and activity and to differentiate various latency types, (iii) the role of the tumor microenvironment in EBV-associated malignancies, (iv) the different immune escape mechanisms and (v) their clinical relevance. This gained information will enhance the development of therapies against EBV-mediated diseases to improve patient outcome.
Highlights
The Epstein–Barr virus (EBV), described in 1964 by Michael Anthony Epstein and Yvonne Barr in African endemic Burkitt lymphoma (BL) samples, was the first discovered human-tumor-associated virus [1,2]
This review provides an overview of the characteristic features of EBV with a focus on the intrinsic and extrinsic immune evasion strategies, which contribute to EBV-associated malignancies
The tumor microenvironment (TME) plays a central role in local cancer control by recruiting and differentiating immune-suppressive and/or anti-inflammatory cells, such as regulatory T cells (Tregs), Th17 cells, dendritic cells (DCs), M2 tumor-associated macrophages (TAMs) and myeloidderived suppressor cells (MDSCs), and inhibiting immune effector cells such as natural killer (NK) cells and CD8+ T lymphocytes, which leads to the establishment of an immunosuppressive TME [125]
Summary
The Epstein–Barr virus (EBV), described in 1964 by Michael Anthony Epstein and Yvonne Barr in African endemic Burkitt lymphoma (BL) samples, was the first discovered human-tumor-associated virus [1,2]. This knowledge provided important insights into the involvement of viruses in the pathogenesis of human malignancies and the natural history of human herpes viruses (HHVs). Chronic EBV infection of different tissues of mainly epithelial and lymphocytic origin has been associated with malignant diseases such as carcinomas, lymphomas/lymphoproliferative disorders and soft-tissue tumors [17,18,19,20,21].
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