The Role of NK Cells in EBV Infection and EBV-Associated NPC

Abstract

A vast majority of the population worldwide are asymptomatic carriers of Epstein-Barr Virus (EBV). However, some infected individuals eventually develop EBV-related cancers, including Nasopharyngeal Carcinoma (NPC). NPC is one of the most common EBV-associated epithelial cancers, and is highly prevalent in Southern China and Southeast Asia. While NPC is highly sensitive to radiotherapy and chemotherapy, there is a lack of effective and durable treatment among the 15%-30% of patients who subsequently develop recurrent disease. Natural Killer (NK) cells are natural immune lymphocytes that are innately primed against virus-infected cells and nascent aberrant transformed cells. As EBV is found in both virally infected and cancer cells, it is of interest to examine the NK cells' role in both EBV infection and EBV-associated NPC. Herein, we review the current understanding of how EBV-infected cells are cleared by NK cells, and how EBV can evade NK cell-mediated elimination in the context of type II latency in NPC. Next, we summarize the current literature about NPC and NK cell biology. Finally, we discuss the translational potential of NK cells in NPC. This information will deepen our understanding of host immune interactions with EBV-associated NPC and facilitate development of more effective NK-mediated therapies for NPC treatment.

Keywords: Epstein-Barr Virus (EBV); NK cells; Nasopharyngeal Carcinoma (NPC).

Figure 1

Graphical summary of the interactions between NK cells and EBV-infected cells. EBV infects both B cells (a,b) and epithelial cells (c,d) in either lytic or latent forms. Peripheral CD56^dimNKG2A⁺KIR^- NK cells (blue) and tonsillar CD56^brightNKG2A⁺ NK cells (orange) have been identified to be the main NK subset in restricting EBV-infection in B lymphocytes. The reactivity of these subsets against EBV-infected epithelial cells remains unclear. (a) During the lytic phase, EBV-infected B lymphocytes are more sensitized to NK killing due to changes in the expression of NK receptor ligands (HLA class I molecules, HLA-E, ULBP-1, CD122) and induction of lytic cycle protein BZLF1. (b) During the latent phase, there is greater NK evasion in infected B cells due to the expression of miR-BARTs, latent membrane antigens (LMP1, LMP2A/B) and other virus-encoded proteins (vBcl-2, vIL10). The miR-BARTs and LMP2A downregulate NKG2D ligands and diminish NK activation potential. The anti-apoptotic protein, vBcl2, provides protection against NK-mediated apoptosis, while pre-latent phase protein vIL-10 prevents lytic reactivation in EBV-infected tonsillar B cells. Additionally, the upregulation of HLA class I molecules can dampen NK activation through the engagement of inhibitory receptors. (c) EBV lytic infection in normal epithelial cells leads to cytopathy, while lytic reactivation in NPC results in genomic instability. However, how this affects evasion or sensitization to NK cells remains unclear. (d) In type II latency, EBV-infected epithelial cells can escape NK attack through the overexpression of PDL-1, which promote NK exhaustion and/or the overexpression of MACC1 which leads to increased TGF-β1 production. Additionally, expression of miR-BARTs, latent membrane proteins and NK inhibitory ligands (HLA-C, HLA-E), and ligation of co-inhibitory receptors on NK (Galectin-9-TIM3, Nectin1-CD96 and Nectin2-TIGIT) may also desensitize antitumor NK responses. In contrast, the downregulation of HLA class I molecules, common in NPC, may sensitize tumor cells to NK cells due to lack of NK inhibitory ligands (“missing-self”). HLA, human leukocyte antigen; ULBP-1, UL16 binding protein 1; BZLF1, BamHI Z fragment leftward open reading frame 1; BART, BamHI-A rightward transcripts; LMP, latent membrane protein; MACC1, metastasis-associated colon cancer-1; vBcl2, viral Bcl-2 homolog; vIL10, viral interleukin-10; PDL-1, programmed cell death protein ligand 1, TGF-β1, transforming growth factor-β 1; NKG2, natural killer group 2; TIM3, T-cell immunoglobulin and mucin domain 3; TIGIT, T cell immunoreceptor with immunoglobulin and ITIM domains.