Epstein-Barr Virus Epithelial Cancers-A Comprehensive Understanding to Drive Novel Therapies

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2021 Dec 27

PMID 34956172

Citations 23

Authors

Shuting Han

Joshua K Tay

Celestine Jia Ling Loh

Axel Jun Ming Chu

Joe Poh Sheng Yeong

Chwee Ming Lim

Han Chong Toh

Affiliations

Soon will be listed here.

Abstract

Epstein-Barr virus (EBV) is a ubiquitous oncovirus associated with specific epithelial and lymphoid cancers. Among the epithelial cancers, nasopharyngeal carcinoma (NPC), lymphoepithelioma-like carcinoma (LELC), and EBV-associated gastric cancers (EBVaGC) are the most common. The role of EBV in the pathogenesis of NPC and in the modulation of its tumour immune microenvironment (TIME) has been increasingly well described. Much less is known about the pathogenesis and tumour-microenvironment interactions in other EBV-associated epithelial cancers. Despite the expression of EBV-related viral oncoproteins and a generally immune-inflamed cancer subtype, EBV-associated epithelial cancers have limited systemic therapeutic options beyond conventional chemotherapy. Immune checkpoint inhibitors are effective only in a minority of these patients and even less efficacious with molecular targeting drugs. Here, we examine the key similarities and differences of NPC, LELC, and EBVaGC and comprehensively describe the clinical, pathological, and molecular characteristics of these cancers. A deeper comparative understanding of these EBV-driven cancers can potentially uncover targets in the tumour, TIME, and stroma, which may guide future drug development and cast light on resistance to immunotherapy.

Citing Articles

A Novel Inflammation-Marker-Based Prognostic Model for Advanced Pulmonary Lymphoepithelioma-Like Carcinoma.

Chen X, Liu T, Mo S, Yang Y, Chen X, Hong S J Inflamm Res. 2025; 18:2433-2445.

PMID: 40008083 PMC: 11859127. DOI: 10.2147/JIR.S502286.

Hip metastasis presenting as anterior knee pain from nasopharyngeal carcinoma: A case report.

Lang J, Xiong Z Oncol Lett. 2025; 29(4):165.

PMID: 39944789 PMC: 11811695. DOI: 10.3892/ol.2025.14911.

The Treatment of Primary Lymphoepithelioma-Like Carcinoma in the Head and Neck and Nasopharyngeal Carcinoma.

Lin Q, Du M, Yan S, Zhang X, Li X, Zhang Y Cancer Med. 2024; 13(22):e70389.

PMID: 39540315 PMC: 11561518. DOI: 10.1002/cam4.70389.

Prediction of viral oncoproteins through the combination of generative adversarial networks and machine learning techniques.

Beltran J, Herrera-Belen L, Yanez A, Jimenez L Sci Rep. 2024; 14(1):27108.

PMID: 39511292 PMC: 11543823. DOI: 10.1038/s41598-024-77028-y.

Gammaherpesvirus Infection Stimulates Lung Tumor-Promoting Inflammation.

Mukhopadhyay S, Swan K, Pridjian G, Kolls J, Zhuang Y, Yin Q Pathogens. 2024; 13(9).

PMID: 39338937 PMC: 11434807. DOI: 10.3390/pathogens13090747.

References

Tong Z, Cai M, Wang X, Kong L, Mai S, Liu Y . EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin. Oncogene. 2011; 31(5):583-94. DOI: 10.1038/onc.2011.254. View

Smith C, McGrath M, Neller M, Matthews K, Crooks P, Le Texier L . Complete response to PD-1 blockade following EBV-specific T-cell therapy in metastatic nasopharyngeal carcinoma. NPJ Precis Oncol. 2021; 5(1):24. PMC: 7979738. DOI: 10.1038/s41698-021-00162-7. View

Churlaud G, Pitoiset F, Jebbawi F, Lorenzon R, Bellier B, Rosenzwajg M . Human and Mouse CD8(+)CD25(+)FOXP3(+) Regulatory T Cells at Steady State and during Interleukin-2 Therapy. Front Immunol. 2015; 6:171. PMC: 4397865. DOI: 10.3389/fimmu.2015.00171. View

Zhang J, Jia L, Lin W, Yip Y, Lo K, Lau V . Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Upregulates Glucose Transporter 1 Transcription via the mTORC1/NF-κB Signaling Pathways. J Virol. 2017; 91(6). PMC: 5331802. DOI: 10.1128/JVI.02168-16. View

Chen J, He D, Tang F, Shao C . Epstein-Barr virus-associated gastric carcinoma: a newly defined entity. J Clin Gastroenterol. 2012; 46(4):262-71. DOI: 10.1097/MCG.0b013e318249c4b8. View

Zhong J, Min L, Huang H, Li L, Li D, Li J . EZH2 regulates the expression of p16 in the nasopharyngeal cancer cells. Technol Cancer Res Treat. 2013; 12(3):269-74. DOI: 10.7785/tcrt.2012.500315. View

Chang K, Chang Y, Wu C, Liu Y, Chen M, Tsang N . Multiplexed immunobead-based profiling of cytokine markers for detection of nasopharyngeal carcinoma and prognosis of patient survival. Head Neck. 2011; 33(6):886-97. DOI: 10.1002/hed.21557. View

Wang Y, Li M, Guo Y, Huang H, Dong X, Sun Y . Key genes affecting the progression of nasopharyngeal carcinoma identified by RNA-sequencing and bioinformatic analysis. Aging (Albany NY). 2021; 13(18):22176-22187. PMC: 8507278. DOI: 10.18632/aging.203521. View

Okabe A, Funata S, Matsusaka K, Namba H, Fukuyo M, Rahmutulla B . Regulation of tumour related genes by dynamic epigenetic alteration at enhancer regions in gastric epithelial cells infected by Epstein-Barr virus. Sci Rep. 2017; 7(1):7924. PMC: 5554293. DOI: 10.1038/s41598-017-08370-7. View

10.

Tsai C, Li H, Lu Y, Hsueh C, Liang Y, Chen C . Activation of DNA methyltransferase 1 by EBV LMP1 Involves c-Jun NH(2)-terminal kinase signaling. Cancer Res. 2006; 66(24):11668-76. DOI: 10.1158/0008-5472.CAN-06-2194. View

11.

Xu F, Xiong D, Xu Y, Cao S, Xue W, Qin H . An epidemiological and molecular study of the relationship between smoking, risk of nasopharyngeal carcinoma, and Epstein-Barr virus activation. J Natl Cancer Inst. 2012; 104(18):1396-410. DOI: 10.1093/jnci/djs320. View

12.

Zhao W, Deng N, Gao X, Chen T, Xie J, Li Q . Primary lymphoepithelioma-like carcinoma of salivary glands: a clinicopathological study of 21 cases. Int J Clin Exp Pathol. 2015; 7(11):7951-6. PMC: 4270609. View

13.

Pathmanathan R, Prasad U, Sadler R, Flynn K, Raab-Traub N . Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl J Med. 1995; 333(11):693-8. DOI: 10.1056/NEJM199509143331103. View

14.

Luftig M, Yasui T, Soni V, Kang M, Jacobson N, Cahir-McFarland E . Epstein-Barr virus latent infection membrane protein 1 TRAF-binding site induces NIK/IKK alpha-dependent noncanonical NF-kappaB activation. Proc Natl Acad Sci U S A. 2003; 101(1):141-6. PMC: 314152. DOI: 10.1073/pnas.2237183100. View

15.

Taylor G, Steven N . Therapeutic vaccination strategies to treat nasopharyngeal carcinoma. Chin Clin Oncol. 2016; 5(2):23. DOI: 10.21037/cco.2016.03.20. View

16.

Chang Y, Wu C, Shih J, Lee Y . New aspects in clinicopathologic and oncogene studies of 23 pulmonary lymphoepithelioma-like carcinomas. Am J Surg Pathol. 2002; 26(6):715-23. DOI: 10.1097/00000478-200206000-00004. View

17.

Hino R, Uozaki H, Murakami N, Ushiku T, Shinozaki A, Ishikawa S . Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma. Cancer Res. 2009; 69(7):2766-74. DOI: 10.1158/0008-5472.CAN-08-3070. View

18.

Zhang H, Li Y, Wang H, Zhang A, Chen M, Fang Z . Ephrin receptor A2 is an epithelial cell receptor for Epstein-Barr virus entry. Nat Microbiol. 2018; 3(2):1-8. DOI: 10.1038/s41564-017-0080-8. View

19.

Zhang L, MacIsaac K, Zhou T, Huang P, Xin C, Dobson J . Genomic Analysis of Nasopharyngeal Carcinoma Reveals TME-Based Subtypes. Mol Cancer Res. 2017; 15(12):1722-1732. DOI: 10.1158/1541-7786.MCR-17-0134. View

20.

Solinas A, Calvisi D . Lessons from rare tumors: hepatic lymphoepithelioma-like carcinomas. World J Gastroenterol. 2015; 21(12):3472-9. PMC: 4375568. DOI: 10.3748/wjg.v21.i12.3472. View