Epstein-Barr Virus as a Promising Immunotherapeutic Target for Nasopharyngeal Carcinoma Treatment

Epstein-Barr virus (EBV) is a pathogen that infects more than 90% of global human population. EBV primarily targets B-lymphocytes and epithelial cells while some of them infect monocyte/macrophage, T-lymphocytes, and dendritic cells (DCs). EBV infection does not cause death by itself but the infection has been persistently associated with certain type of cancers such as nasopharyngeal carcinoma (NPC), Burkitt’s lymphoma (BL), and Hodgkin’s lymphoma (HL). Recent findings have shown promise on targeting EBV proteins for cancer therapy by immunotherapeutic approach. Some studies have also shown the success of adopting EBV-based therapeutic vaccines for the prevention of EBV-associated cancer particularly on NPC. In-depth investigations are in progress to refine the current therapeutic and vaccination strategies. In present review, we discuss the highly potential EBV targets for NPC immunotherapy and therapeutic vaccine development as well as addressing the underlying challenges in the process of bringing the therapy and vaccination from the bench to bedside.

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The initial study of EBNA-2 polymorphisms in nasopharyngeal carcinoma in Vietnam

ENGINEERING AND TECHNOLOGY ◽

10.46223/hcmcoujs.tech.en.8.1.337.2018 ◽

2020 ◽

Vol 8 (1) ◽

pp. 60-67

Author(s):

Ngo Dong Kha ◽

Huynh Thi Mong Tuyen ◽

Lam Hong Ngoc ◽

Thieu Hong Hue ◽

Le Quang Anh Tuan ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Initial Data ◽

Epstein Barr Virus ◽

Initial Study ◽

Nucleotide Sequencing ◽

Potential Contribution ◽

Barr Virus ◽

Ebv Infection ◽

Vietnamese Population ◽

Epstein Barr

Epstein-Barr virus (EBV) infection is the main cause of Nasopharyngeal Carcinoma (NPC). EBNA-2, one of the most important genes participating in the formation of NPC, also helps EBV evade an attack on the immune system. EBNA-2 has 4 variants including E2-A, E2-B, E2-C and E-2D, of which E2-A and E2-C are the characterized variants for NPC. This study aimed to evaluate the variations of EBNA-2 in NPC biopsy samples of Vietnamese patients. This initial study used 10 biopsy samples, which were positively confirmed to NPC, collected from Cho Ray Hospital. Nested PCR – nucleotide sequencing was applied to analyze the variants of EBNA-2. The results showed that 8 out of 10 samples, accounting for 80%, were positive to EBNA-2. Additionally, only two variants, E-2A and E-2C were detected in our study, in which, E2-A subtype was identified as the predominant subtype. These findings would provide initial data about potential contribution of EBNA-2 polymorphisms to etiology of NPC in Vietnamese population.

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Epstein-Barr Virus Mediated Signaling in Nasopharyngeal Carcinoma Carcinogenesis

Cancers ◽

10.3390/cancers12092441 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2441 ◽

Cited By ~ 1

Author(s):

Timmy Richardo ◽

Pongphol Prattapong ◽

Chawalit Ngernsombat ◽

Nurulfitri Wisetyaningsih ◽

Hisashi Iizasa ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Southeast Asia ◽

Signaling Pathways ◽

Epstein Barr Virus ◽

Barr Virus ◽

Ebv Infection ◽

Non Coding Rnas ◽

Epstein Barr ◽

Exact Relationship

Nasopharyngeal carcinoma (NPC) is one of the most common tumors occurring in China and Southeast Asia. Etiology of NPC seems to be complex and involves many determinants, one of which is Epstein-Barr virus (EBV) infection. Although evidence demonstrates that EBV infection plays a key role in NPC carcinogenesis, the exact relationship between EBV and dysregulation of signaling pathways in NPC needs to be clarified. This review focuses on the interplay between EBV and NPC cells and the corresponding signaling pathways, which are modulated by EBV oncoproteins and non-coding RNAs. These altered signaling pathways could be critical for the initiation and progression of NPC.

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Link of Nasopharyngeal Carcinoma and Epstein-Barr Virus

Biology Medicine & Natural Product Chemistry ◽

10.14421/biomedich.2018.72.51-55 ◽

2018 ◽

Vol 7 (2) ◽

pp. 51-55

Author(s):

Sugiyanto Sugiyanto ◽

Lina Aryati ◽

Fajar Adi Kusumo ◽

Mardiah Suci Hardianti

Keyword(s):

Nasopharyngeal Carcinoma ◽

Epstein Barr Virus ◽

Carcinoma Cells ◽

Lymphoid Cells ◽

Epithelial Tissue ◽

Barr Virus ◽

Ebv Infection ◽

Ebv Dna ◽

Epstein Barr ◽

Basic Level

Nasopharyngeal Carcinoma (NPC) is a cancer that occurs in nasopharynx which is associated with Epstein-Barr Virus (EBV). Mutation agents in nasopharyngeal neoplasms occur because of EBV infection. Transformation of B-cells due to EBV causes hormone imbalance in lymphoid cells or nasopharyngeal epithelial tissue. Rates of EBV infection have been shown to be prognostic to NPC. The basic level of EBV DNA can be used for stratification prognosis, with higher titers showing greater disease severity and worse outcomes. With mathematical models, there is a correlation between the increase in Epstein-Barr Virus and the increase in Invasive Carcinoma Cells or increase in Nasopharyngeal Carcinoma Cells.

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Role of Epstein-Barr virus in the development of nasopharyngeal carcinoma

Open Medicine ◽

10.1515/med-2017-0025 ◽

2017 ◽

Vol 12 (1) ◽

pp. 171-176 ◽

Cited By ~ 6

Author(s):

Hui Zhang ◽

Jing Wang ◽

Dan Yu ◽

Yan Liu ◽

Kai Xue ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Epstein Barr Virus ◽

Southern China ◽

Latent Membrane Protein 1 ◽

Barr Virus ◽

Ebv Infection ◽

Micro Rnas ◽

Total Cancer ◽

Epstein Barr

AbstractSouthern China experiences larger extent of total cancer pathologies, of which nasopharyngeal carcinoma has the highest incidence under otorhinolaryngeal malignant carcinomas. Risk factor of nasopharyngeal carcinoma varies from hereditary causes to virus infection, among which Epstein-Barr virus (EBV) infection is the mostly investigated. The study into mechanism of EBV in occurrence, development and prognosis of nasopharyngeal carcinoma has been studied for several decades. The pathophysiology in making of EBV into a cancerogen includes proteins as latent membrane protein 1 (LMPs) and nucleic acids as micro-RNAs. In this paper, we reviewed till date studies focusing on relationship between EBV and nasopharyngeal carcinoma.

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Regulation of DNA Damage Signaling and Cell Death Responses by Epstein-Barr Virus Latent Membrane Protein 1 (LMP1) and LMP2A in Nasopharyngeal Carcinoma Cells

Journal of Virology ◽

10.1128/jvi.00958-15 ◽

2015 ◽

Vol 89 (15) ◽

pp. 7612-7624 ◽

Cited By ~ 16

Author(s):

Laura R. Wasil ◽

Leizhen Wei ◽

Christopher Chang ◽

Li Lan ◽

Kathy H. Y. Shair

Keyword(s):

Dna Damage ◽

Cell Death ◽

Dna Repair ◽

Nasopharyngeal Carcinoma ◽

Epstein Barr Virus ◽

Combined Effects ◽

Barr Virus ◽

Ebv Infection ◽

Dna Damage Signaling ◽

Epstein Barr

ABSTRACTNasopharyngeal carcinoma (NPC) is closely associated with latent Epstein-Barr virus (EBV) infection. Although EBV infection of preneoplastic epithelial cells is not immortalizing, EBV can modulate oncogenic and cell death mechanisms. The viral latent membrane proteins 1 (LMP1) and LMP2A are consistently expressed in NPC and can cooperate in bitransgenic mice expressed from the keratin-14 promoter to enhance carcinoma development in an epithelial chemical carcinogenesis model. In this study, LMP1 and LMP2A were coexpressed in the EBV-negative NPC cell line HK1 and examined for combined effects in response to genotoxic treatments. In response to DNA damage activation, LMP1 and LMP2A coexpression reduced γH2AX (S139) phosphorylation and caspase cleavage induced by a lower dose (5 μM) of the topoisomerase II inhibitor etoposide. Regulation of γH2AX occurred before the onset of caspase activation without modulation of other DNA damage signaling mediators, including ATM, Chk1, or Chk2, and additionally was suppressed by inducers of DNA single-strand breaks (SSBs) and replication stress. Despite reduced DNA damage repair signaling, LMP1-2A coexpressing cells recovered from cytotoxic doses of etoposide; however, LMP1 expression was sufficient for this effect. LMP1 and LMP2A coexpression did not enhance cell growth, with a moderate increase of cell motility to fibronectin. This study supports that LMP1 and LMP2A jointly regulate DNA repair signaling and cell death activation with no further enhancement in the growth properties of neoplastic cells.IMPORTANCENPC is characterized by clonal EBV infection and accounts for >78,000 annual cancer cases with increased incidence in regions where EBV is endemic, such as southeast Asia. The latent proteins LMP1 and LMP2A coexpressed in NPC can individually enhance growth or survival properties in epithelial cells, but their combined effects and potential regulation of DNA repair and checkpoint mechanisms are relatively undetermined. In this study, LMP1-2A coexpression suppressed activation of the DNA damage response (DDR) protein γH2AX induced by selective genotoxins that promote DNA replication stress or SSBs. Expression of LMP1 was sufficient to recover cells, resulting in outgrowth of LMP1 and LMP1-2A-coexpressing cells and indicating distinct LMP1-dependent effects in the restoration of replicative potential. These findings demonstrate novel properties for LMP1 and LMP2A in the cooperative modulation of DDR and apoptotic signaling pathways, further implicating both proteins in the progression of NPC and epithelial malignancies.

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Epstein-Barr Virus Latent Membrane Protein-1 Expression in Nasopharyngeal Carcinoma

JCO Global Oncology ◽

10.1200/go.21.00120 ◽

2021 ◽

pp. 1406-1412

Author(s):

Valerie E. Salano ◽

Amos R. Mwakigonja ◽

Ashfaq Abdulshakoor ◽

Aveline A. Kahinga ◽

Enica M. Richard

Keyword(s):

Nasopharyngeal Carcinoma ◽

Membrane Protein ◽

Epstein Barr Virus ◽

Latent Membrane Protein ◽

Latent Membrane Protein 1 ◽

Female Ratio ◽

Histologic Subtype ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr

PURPOSE Nasopharyngeal carcinoma (NPC), a malignant neoplasm of the epithelium covering the nasopharynx, is a rare disease in most parts of the world. Epstein-Barr virus (EBV), the most potent oncogenic virus, coupled with environmental and genetic factors has been identified to play a role in the development of NPC. An array of methods for detecting the virus do exist, from serologic detection of antibodies to DNA amplification. There is paucity of local data on the status of EBV infection in relation to NPC within the region, and this study attempts to shed more light on the subject. METHODS This was a retrospective cross-sectional laboratory-based study on histologically confirmed, archived tissues from July 2015 to June 2019. Immunohistochemistry expression of latent membrane protein-1 (LMP-1) was used to detect EBV infection in the tissues. RESULTS A total of 71 cases were enrolled in this study. The mean age was 47.87 years ± 16.84 years with a male-to-female ratio of 1.5:1. There was a unimodal distribution of EBV detection, with the peak (26.8%) at 36-45 years. About 45.1% of the 71 samples tested positive for LMP-1, all of which were nonkeratinizing carcinoma. Nonkeratinizing carcinoma was the most common histopathologic subtype (n = 67; 94.4%), with the majority (38 of 67; 56.7%) being undifferentiated and 29 of 67 (43.3%) differentiated. Keratinizing and basaloid subtypes had two cases each, representing 2.8%. CONCLUSION A significant proportion of NPC, particularly nonkeratinizing histologic subtype, seems to show LMP-1 positivity by immunohistochemistry, which may be adopted in resource-constrained settings to detect EBV infection in these tissue biopsies.

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Faktor-faktor penyebab terjadinya karsinoma nasofaring (KNF)

Wellness And Healthy Magazine ◽

10.30604/well.72212020 ◽

2020 ◽

Vol 2 (1) ◽

pp. 113-120

Author(s):

Nur Suci Amanah

Keyword(s):

Nasopharyngeal Carcinoma ◽

Epithelial Cells ◽

Epstein Barr Virus ◽

Dietary Habits ◽

Common Disease ◽

Salted Fish ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr ◽

Nasopharyngeal Epithelial

Nasopharyngeal carcinoma is a common disease in southern China. The etiologies of the main factors proposed for the pathogenesis of KNF include genetic factors, environmental factors and Epstein Barr Virus (EBV) infection. Other causes besides preserved food consumption include salted fish which have been involved in the etiology of NPC. The downward trend in the incidence of NPC has occurred in Hong Kong for the past 20 years, which is caused by changes in dietary habits. Despite the close relationship of EBV infection with NPC, the etiological role of EBV in the pathogenesis of NPC remains an interaction. EBV infection in primary nasopharyngeal epithelial cells occurs. Epstein Barr virus does not convert primary nasopharyngeal epithelial cells into proliferative clones, which is in sharp contrast to the well-documented ability of EBV to alter and perpetuate primary B cells. Genetic changes that are supported in the nasopharyngeal epithelium may be needed to support stable EBV infection. Non-viral factors as a cause of nasopharyngeal carcinoma still cannot be resolved with certainty. Non-viral factors are one of the risk factors that can increase the number of events arising from nasopharyngeal malignancies such as smoke, salted fish, formaldehyde, genetic, as soon as possible firewood, wood dust, chronic infection, throat protector, alcohol and traditional medicine.

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Epstein–Barr virus infection and nasopharyngeal carcinoma

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0270 ◽

2017 ◽

Vol 372 (1732) ◽

pp. 20160270 ◽

Cited By ~ 85

Author(s):

Sai Wah Tsao ◽

Chi Man Tsang ◽

Kwok Wai Lo

Keyword(s):

Nasopharyngeal Carcinoma ◽

Epithelial Cells ◽

Epstein Barr Virus ◽

Lytic Replication ◽

Epstein Barr Virus Infection ◽

Barr Virus ◽

Ebv Infection ◽

Southern Chinese ◽

Genomic Study ◽

Epstein Barr

Epstein–Barr virus (EBV) is associated with multiple types of human cancer, including lymphoid and epithelial cancers. The closest association with EBV infection is seen in undifferentiated nasopharyngeal carcinoma (NPC), which is endemic in the southern Chinese population. A strong association between NPC risk and the HLA locus at chromosome 6p has been identified, indicating a link between the presentation of EBV antigens to host immune cells and NPC risk. EBV infection in NPC is clonal in origin, strongly suggesting that NPC develops from the clonal expansion of a single EBV-infected cell. In epithelial cells, the default program of EBV infection is lytic replication. However, latent infection is the predominant mode of EBV infection in NPC. The establishment of latent EBV infection in pre-invasive nasopharyngeal epithelium is believed to be an early stage of NPC pathogenesis. Recent genomic study of NPC has identified multiple somatic mutations in the upstream negative regulators of NF-κB signalling. Dysregulated NF-κB signalling may contribute to the establishment of latent EBV infection in NPC. Stable EBV infection and the expression of latent EBV genes are postulated to drive the transformation of pre-invasive nasopharyngeal epithelial cells to cancer cells through multiple pathways. This article is part of the themed issue ‘Human oncogenic viruses’.

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Association between Antibody Responses to Epstein-Barr Virus Glycoproteins, Neutralization of Infectivity, and the Risk of Nasopharyngeal Carcinoma

mSphere ◽

10.1128/msphere.00901-20 ◽

2020 ◽

Vol 5 (6) ◽

Author(s):

Qian-Ying Zhu ◽

Xiang-Wei Kong ◽

Cong Sun ◽

Shang-Hang Xie ◽

Allan Hildesheim ◽

...

Keyword(s):

Immune Response ◽

Nasopharyngeal Carcinoma ◽

Humoral Immune Response ◽

Epstein Barr Virus ◽

Healthy Controls ◽

Humoral Immune ◽

Barr Virus ◽

Ebv Infection ◽

Epstein Barr ◽

Antibody Levels

ABSTRACT While Epstein-Barr virus (EBV) is the major cause of nasopharyngeal carcinoma (NPC), the value of the humoral immune response to EBV glycoproteins and NPC development remains unclear. Correlation between antiglycoprotein antibody levels, neutralization of EBV infectivity, and the risk of NPC requires systematic study. Here, we applied a cytometry-based method and enzyme-linked immunosorbent assay to measure neutralization of infectivity and antibody response to EBV glycoproteins (gH/gL, gB, gp350, and gp42) of plasma samples from 20 NPC cases and 20 high-risk and 20 low-risk healthy controls nested within a screening cohort in Sihui, southern China. We found that NPC cases have similar plasma neutralizing activity in both B cells and epithelial cells and EBV glycoprotein-specific IgA and IgG antibody levels compared with those of healthy controls. Significant correlations were observed between gH/gL IgG and gB IgG and the neutralizing ability against EBV infection of epithelial cells and B cells. These results indicate that a high level of glycoprotein antibodies may favor protection against primary EBV infection, instead of being low-risk biomarkers for NPC in long-term EBV-infected adults. In conclusion, this study provides novel insights into the humoral immune response to EBV infection and NPC development, providing valuable leads for future research that is important for prevention and treatment of EBV-related diseases. IMPORTANCE Epstein-Barr virus (EBV) is a human oncogenic gammaherpesvirus that infects over 90% of humans in the world and is causally associated with a spectrum of epithelial and B-cell malignancies such as nasopharyngeal carcinoma (NPC). A prophylactic vaccine against EBV is called for, but no approved vaccine is available yet. Therefore, EBV remains a major public health concern. To facilitate novel vaccines and therapeutics for NPC, it is of great importance to explore the impact of humoral immune response to EBV glycoproteins before the development of NPC. Therefore, in this study, we systematically assessed the correlation between antiglycoprotein antibody levels, neutralization of EBV infectivity, and the risk of NPC development. These results provide valuable information that will contribute to designing effective prevention and treatment strategies for EBV-related diseases such as NPC.

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Predictors of Epstein-Barr virus serostatus in young people in England

BMC Infectious Diseases ◽

10.1186/s12879-019-4578-y ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 3

Author(s):

Joanne R. Winter ◽

Graham S. Taylor ◽

Olivia G. Thomas ◽

Charlotte Jackson ◽

Joanna E. A. Lewis ◽

...

Keyword(s):

Risk Factors ◽

Young People ◽

Epstein Barr Virus ◽

Demographic Data ◽

Early Adulthood ◽

Cross Sectional ◽

Barr Virus ◽

Vaccination Strategies ◽

Ebv Infection ◽

Epstein Barr

Abstract Background Epstein-Barr virus (EBV) is an important human pathogen which causes lifelong infection of > 90% people globally and is linked to infectious mononucleosis (arising from infection in the later teenage years) and several types of cancer. Vaccines against EBV are in development. In order to determine the most cost-effective public health strategy for vaccine deployment, setting-specific data on the age at EBV acquisition and risk factors for early infection are required. Such data are also important to inform mathematical models of EBV transmission that can determine the required target product profile of vaccine characteristics. We thus aimed to examine risk factors for EBV infection in young people in England, in order to improve our understanding of EBV epidemiology and guide future vaccination strategies. Methods The Health Survey for England (HSE) is an annual, cross-sectional representative survey of households in England during which data are collected via questionnaires and blood samples. We randomly selected individuals who participated in the HSE 2002, aiming for 25 participants of each sex in each single year age group from 11 to 24 years. Stored samples were tested for EBV and cytomegalovirus (CMV) antibodies. We undertook descriptive and regression analyses of EBV seroprevalence and risk factors for infection. Results Demographic data and serostatus were available for 732 individuals. EBV seroprevalence was strongly associated with age, increasing from 60.4% in 11–14 year olds throughout adolescence (68.6% in 15–18 year olds) and stabilising by early adulthood (93.0% in those aged 22–24 years). In univariable and multivariable logistic regression models, ethnicity was associated with serostatus (adjusted odds ratio for seropositivity among individuals of other ethnicity versus white individuals 2.33 [95% confidence interval 1.13–4.78]). Smoking was less strongly associated with EBV seropositivity. Conclusions By the age of 11 years, EBV infection is present in over half the population, although age is not the only factor associated with serostatus. Knowledge of the distribution of infection in the UK population is critical for determining future vaccination policies, e.g. comparing general versus selectively targeted vaccination strategies.

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