Impact of Epstein Barr Virus Infection on Treatment Opportunities in Patients with Nasopharyngeal Cancer

Abstract

Chemical, physical, and infectious agents may induce carcinogenesis, and in the latter case, viruses are involved in most cases. The occurrence of virus-induced carcinogenesis is a complex process caused by an interaction across multiple genes, mainly depending by the type of the virus. Molecular mechanisms at the basis of viral carcinogenesis, mainly suggest the involvement of a dysregulation of the cell cycle. Among the virus-inducing carcinogenesis, Epstein Barr Virus (EBV) plays a major role in the development of both hematological and oncological malignancies and importantly, several lines of evidence demonstrated that nasopharyngeal carcinoma (NPC) is consistently associated with EBV infection. Cancerogenesis in NPC may be induced by the activation of different EBV "oncoproteins" which are produced during the so called "latency phase" of EBV in the host cells. Moreover, EBV presence in NPC does affect the tumor microenvironment (TME) leading to a strongly immunosuppressed status. Translational implications of the above-mentioned statements are that EBV-infected NPC cells can express proteins potentially recognized by immune cells in order to elicit a host immune response (tumor associated antigens). Three immunotherapeutic approaches have been implemented for the treatment of NPC including active, adoptive immunotherapy, and modulation of immune regulatory molecules by use of the so-called checkpoint inhibitors. In this review, we will highlight the role of EBV infection in NPC development and analyze its possible implications on therapy strategies.

Keywords: Epstein Barr Virus; check-point inhibitors; immunotherapy; nasopharyngeal carcinoma; tumor associated antigens; tumor microenvironment.

Figure 1

There are three forms of latency expressed by EBV-infected cells, each one characterized by a unique expression of EBV-associated proteins and RNAs.

Figure 2

Differences between TME and TIME.

Figure 3

Check-point inhibitors act by removing the so-called “inhibitory brakes”, namely stimuli elicited through particular ligands (CTLA-4 and PD-1 for example) which lead cytotoxic T lymphocytes (CTLs) to anergy. The molecules best known and used in clinical practice are CTLA-4 inhibitors (ipilimumab) and PD-1 inhibitors (nivolumab, pembrolizumab, camtelizumab, and toripalimab).

Figure 4

Current therapy options in NPC overall.