Journal of Gastric Cancer

The Korean Gastric Cancer Association (대한위암학회)
권호 표지
DOI QR코드

DOI QR Code

Epstein-Barr Virus-Associated Gastric Carcinoma and Specific Features of the Accompanying Immune Response

  • Cho, Junhun (Department of Pathology & Translational Genomics, Samsung Medical Center) ;
  • Kang, Myung-Soo (Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University School of Medicine) ;
  • Kim, Kyoung-Mee (Department of Pathology & Translational Genomics, Samsung Medical Center)
  • Received : 2016.03.08
  • Accepted : 2016.03.14
  • Published : 2016.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is one of the four subtypes of gastric carcinoma (GC), as defined by the novel classification recently proposed by The Cancer Genome Atlas. EBVaGC has several clinicopathological features such as longer survival and higher frequency of lymphoepithelioma-like carcinoma (LELC) and carcinoma with Crohn's disease-like lymphoid reaction that distinguish it from EBV-negative GC. The intensity and pattern of host cellular immune response in GC have been found to significantly correlate with the prognosis of patients with GC, suggesting that immune reaction and tumor microenvironment have critical roles in the progression of GC, and in particular, EBVaGC. Here, we reviewed the cellular and molecular mechanisms underlying prominent immune reactions in patients with EBVaGC. In EBVaGC, deregulation of the expression of immune response-related genes promotes marked intra-or peritumoral immune cell infiltration. The expression of programmed death receptor-ligand 1 is known to be increased in EBVaGC, and therefore, it has been proposed as a favorable prognostic factor for patients with EBVaGC, albeit some data supporting this claim are controversial. Overall, the underlying mechanisms and clinical significance of the host cellular immune response in patients with EBVaGC have not been thoroughly elucidated. Therefore, further research is necessary to better understand the role of tumor microenvironment in EBVaGC.

Keywords

References

  1. Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from burkitt's lymphoma. Lancet 1964;1:702-703.
  2. Epstein MA, Barr YM. Cultivation in vitro of human lymphoblasts from burkitt's malignant lymphoma. Lancet 1964;1:252-253.
  3. Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat Rev Cancer 2004;4:757-768. https://doi.org/10.1038/nrc1452
  4. Fukayama M, Hayashi Y, Iwasaki Y, Chong J, Ooba T, Takizawa T, et al. Epstein-Barr virus-associated gastric carcinoma and Epstein-Barr virus infection of the stomach. Lab Invest 1994;71:73-81.
  5. Busson P, Keryer C, Ooka T, Corbex M. EBV-associated nasopharyngeal carcinomas: from epidemiology to virus-targeting strategies. Trends Microbiol 2004;12:356-360. https://doi.org/10.1016/j.tim.2004.06.005
  6. Akiba S, Koriyama C, Herrera-Goepfert R, Eizuru Y. Epstein-Barr virus associated gastric carcinoma: epidemiological and clinicopathological features. Cancer Sci 2008;99:195-201. https://doi.org/10.1111/j.1349-7006.2007.00674.x
  7. Wu MS, Shun CT, Wu CC, Hsu TY, Lin MT, Chang MC, et al. Epstein-Barr virus-associated gastric carcinomas: relation to H. pylori infection and genetic alterations. Gastroenterology 2000;118:1031-1038. https://doi.org/10.1016/S0016-5085(00)70355-6
  8. Kang GH, Lee S, Kim WH, Lee HW, Kim JC, Rhyu MG, et al. Epstein-barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma. Am J Pathol 2002;160:787-794. https://doi.org/10.1016/S0002-9440(10)64901-2
  9. Watanabe H, Enjoji M, Imai T. Gastric carcinoma with lymphoid stroma. Its morphologic characteristics and prognostic correlations. Cancer 1976;38:232-243. https://doi.org/10.1002/1097-0142(197607)38:1<232::AID-CNCR2820380135>3.0.CO;2-4
  10. Lertprasertsuke N, Tsutsumi Y. Gastric carcinoma with lymphoid stroma. Analysis using mucin histochemistry and immunohistochemistry. Virchows Arch A Pathol Anat Histopathol 1989;414:231-241. https://doi.org/10.1007/BF00822027
  11. Minamoto T, Mai M, Watanabe K, Ooi A, Kitamura T, Takahashi Y, et al. Medullary carcinoma with lymphocytic infiltration of the stomach. Clinicopathologic study of 27 cases and immunohistochemical analysis of the subpopulations of infiltrating lymphocytes in the tumor. Cancer 1990;66:945-952. https://doi.org/10.1002/1097-0142(19900901)66:5<945::AID-CNCR2820660523>3.0.CO;2-X
  12. Nakamura S, Ueki T, Yao T, Ueyama T, Tsuneyoshi M. Epstein-Barr virus in gastric carcinoma with lymphoid stroma. Special reference to its detection by the polymerase chain reaction and in situ hybridization in 99 tumors, including a morphologic analysis. Cancer 1994;73:2239-2249. https://doi.org/10.1002/1097-0142(19940501)73:9<2239::AID-CNCR2820730902>3.0.CO;2-#
  13. van Beek J, zur Hausen A, Klein Kranenbarg E, van de Velde CJ, Middeldorp JM, van den Brule AJ, et al. EBV-positive gastric adenocarcinomas: a distinct clinicopathologic entity with a low frequency of lymph node involvement. J Clin Oncol 2004;22:664-670. https://doi.org/10.1200/jco.2004.22.14_suppl.664
  14. Gulley ML, Pulitzer DR, Eagan PA, Schneider BG. Epstein-Barr virus infection is an early event in gastric carcinogenesis and is independent of bcl-2 expression and p53 accumulation. Hum Pathol 1996;27:20-27. https://doi.org/10.1016/S0046-8177(96)90133-1
  15. Chang MS, Lee HS, Kim CW, Kim YI, Kim WH. Clinicopathologic characteristics of Epstein-Barr virus-incorporated gastric cancers in Korea. Pathol Res Pract 2001;197:395-400. https://doi.org/10.1078/0344-0338-00052
  16. Park ES, Do IG, Park CK, Kang WK, Noh JH, Sohn TS, et al. Cyclooxygenase-2 is an independent prognostic factor in gastric carcinoma patients receiving adjuvant chemotherapy and is not associated with EBV infection. Clin Cancer Res 2009;15:291-298. https://doi.org/10.1158/1078-0432.CCR-08-0848
  17. Camargo MC, Kim WH, Chiaravalli AM, Kim KM, Corvalan AH, Matsuo K, et al. Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: an international pooled analysis. Gut 2014;63:236-243. https://doi.org/10.1136/gutjnl-2013-304531
  18. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513:202-209. https://doi.org/10.1038/nature13480
  19. Song HJ, Srivastava A, Lee J, Kim YS, Kim KM, Ki Kang W, et al. Host inflammatory response predicts survival of patients with Epstein-Barr virus-associated gastric carcinoma. Gastroenterology 2010;139:84-92. https://doi.org/10.1053/j.gastro.2010.04.002
  20. Murphy G, Pfeiffer R, Camargo MC, Rabkin CS. Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology 2009;137:824-833. https://doi.org/10.1053/j.gastro.2009.05.001
  21. Lee JH, Kim SH, Han SH, An JS, Lee ES, Kim YS. Clinicopathological and molecular characteristics of Epstein-Barr virusassociated gastric carcinoma: a meta-analysis. J Gastroenterol Hepatol 2009;24:354-365. https://doi.org/10.1111/j.1440-1746.2009.05775.x
  22. Matsunou H, Konishi F, Hori H, Ikeda T, Sasaki K, Hirose Y, et al. Characteristics of Epstein-Barr virus-associated gastric carcinoma with lymphoid stroma in Japan. Cancer 1996;77:1998-2004. https://doi.org/10.1002/(SICI)1097-0142(19960515)77:10<1998::AID-CNCR6>3.0.CO;2-D
  23. Arikawa J, Tokunaga M, Tashiro Y, Tanaka S, Sato E, Haraguchi K, et al. Epstein-Barr virus-positive multiple early gastric cancers and dysplastic lesions: a case report. Pathol Int 1997;47:730-734. https://doi.org/10.1111/j.1440-1827.1997.tb04450.x
  24. Chang MS, Lee HS, Kim HS, Kim SH, Choi SI, Lee BL, et al. Epstein-Barr virus and microsatellite instability in gastric carcinogenesis. J Pathol 2003;199:447-452. https://doi.org/10.1002/path.1302
  25. Camargo MC, Koriyama C, Matsuo K, Kim WH, Herrera- Goepfert R, Liao LM, et al. Case-case comparison of smoking and alcohol risk associations with Epstein-Barr virus-positive gastric cancer. Int J Cancer 2014;134:948-953. https://doi.org/10.1002/ijc.28402
  26. Luo B, Wang Y, Wang XF, Gao Y, Huang BH, Zhao P. Correlation of Epstein-Barr virus and its encoded proteins with Helicobacter pylori and expression of c-met and c-myc in gastric carcinoma. World J Gastroenterol 2006;12:1842-1848. https://doi.org/10.3748/wjg.v12.i12.1842
  27. Yanai H, Murakami T, Yoshiyama H, Takeuchi H, Nishikawa J, Nakamura H, et al. Epstein-Barr virus-associated gastric carcinoma and atrophic gastritis. J Clin Gastroenterol 1999;29:39-43. https://doi.org/10.1097/00004836-199907000-00010
  28. Lima VP, de Lima MA, Andre AR, Ferreira MV, Barros MA, Rabenhorst SH. H pylori (CagA) and Epstein-Barr virus infection in gastric carcinomas: correlation with p53 mutation and c-Myc, Bcl-2 and Bax expression. World J Gastroenterol 2008;14:884-891. https://doi.org/10.3748/wjg.14.884
  29. Song HJ, Kim KM. Pathology of epstein-barr virus-associated gastric carcinoma and its relationship to prognosis. Gut Liver 2011;5:143-148. https://doi.org/10.5009/gnl.2011.5.2.143
  30. Lee HS, Chang MS, Yang HK, Lee BL, Kim WH. Epstein-barr virus-positive gastric carcinoma has a distinct protein expression profile in comparison with epstein-barr virus-negative carcinoma. Clin Cancer Res 2004;10:1698-1705. https://doi.org/10.1158/1078-0432.CCR-1122-3
  31. Saiki Y, Ohtani H, Naito Y, Miyazawa M, Nagura H. Immunophenotypic characterization of Epstein-Barr virus-associated gastric carcinoma: massive infiltration by proliferating CD8+ T-lymphocytes. Lab Invest 1996;75:67-76.
  32. Tokunaga M, Land CE, Uemura Y, Tokudome T, Tanaka S, Sato E. Epstein-Barr virus in gastric carcinoma. Am J Pathol 1993;143:1250-1254.
  33. van Beek J, zur Hausen A, Snel SN, Berkhof J, Kranenbarg EK, van de Velde CJ, et al. Morphological evidence of an activated cytotoxic T-cell infiltrate in EBV-positive gastric carcinoma preventing lymph node metastases. Am J Surg Pathol 2006;30:59-65. https://doi.org/10.1097/01.pas.0000176428.06629.1e
  34. Kuzushima K, Nakamura S, Nakamura T, Yamamura Y, Yokoyama N, Fujita M, et al. Increased frequency of antigenspecific CD8(+) cytotoxic T lymphocytes infiltrating an Epstein-Barr virus-associated gastric carcinoma. J Clin Invest 1999;104:163-171. https://doi.org/10.1172/JCI6062
  35. Iwasaki Y, Chong JM, Hayashi Y, Ikeno R, Arai K, Kitamura M, et al. Establishment and characterization of a human Epstein- Barr virus-associated gastric carcinoma in SCID mice. J Virol 1998;72:8321-8326.
  36. Chong JM, Sakuma K, Sudo M, Osawa T, Ohara E, Uozaki H, et al. Interleukin-1beta expression in human gastric carcinoma with Epstein-Barr virus infection. J Virol 2002;76:6825-6831. https://doi.org/10.1128/JVI.76.13.6825-6831.2002
  37. Strong MJ, Xu G, Coco J, Baribault C, Vinay DS, Lacey MR, et al. Differences in gastric carcinoma microenvironment stratify according to EBV infection intensity: implications for possible immune adjuvant therapy. PLoS Pathog 2013;9:e1003341. https://doi.org/10.1371/journal.ppat.1003341
  38. Kim SY, Park C, Kim HJ, Park J, Hwang J, Kim JI, et al. Deregulation of immune response genes in patients with Epstein-Barr virus-associated gastric cancer and outcomes. Gastroenterology 2015;148:137-147. https://doi.org/10.1053/j.gastro.2014.09.020
  39. Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother 2007;56:739-745. https://doi.org/10.1007/s00262-006-0272-1
  40. Zitvogel L, Kroemer G. Targeting PD-1/PD-L1 interactions for cancer immunotherapy. Oncoimmunology 2012;1:1223-1225. https://doi.org/10.4161/onci.21335
  41. Wu C, Zhu Y, Jiang J, Zhao J, Zhang XG, Xu N. Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem 2006;108:19-24. https://doi.org/10.1016/j.acthis.2006.01.003
  42. Hou J, Yu Z, Xiang R, Li C, Wang L, Chen S, et al. Correlation between infiltration of FOXP3+ regulatory T cells and expression of B7-H1 in the tumor tissues of gastric cancer. Exp Mol Pathol 2014;96:284-291. https://doi.org/10.1016/j.yexmp.2014.03.005
  43. Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, et al. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 2010;116:1757-1766. https://doi.org/10.1002/cncr.24899
  44. Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 2012;4:127ra37.
  45. Gadiot J, Hooijkaas AI, Kaiser AD, van Tinteren H, van Boven H, Blank C. Overall survival and PD-L1 expression in metastasized malignant melanoma. Cancer 2011;117:2192-2201. https://doi.org/10.1002/cncr.25747
  46. Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res 2005;11:2947-2953. https://doi.org/10.1158/1078-0432.CCR-04-1469
  47. Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term followup. Cancer Res 2006;66:3381-3385. https://doi.org/10.1158/0008-5472.CAN-05-4303
  48. Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother 2007;56:1173-1182. https://doi.org/10.1007/s00262-006-0266-z
  49. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res 2007;13:2151-2157. https://doi.org/10.1158/1078-0432.CCR-06-2746
  50. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed cell death 1 ligand 1 and tumorinfiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A 2007;104:3360-3365. https://doi.org/10.1073/pnas.0611533104
  51. Zeng Z, Shi F, Zhou L, Zhang MN, Chen Y, Chang XJ, et al. Upregulation of circulating PD-L1/PD-1 is associated with poor post-cryoablation prognosis in patients with HBV-related hepatocellular carcinoma. PLoS One 2011;6:e23621. https://doi.org/10.1371/journal.pone.0023621
  52. Lipson EJ, Vincent JG, Loyo M, Kagohara LT, Luber BS, Wang H, et al. PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival. Cancer Immunol Res 2013;1:54-63. https://doi.org/10.1158/2326-6066.CIR-13-0034
  53. Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, et al. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest 2014;94:107-116. https://doi.org/10.1038/labinvest.2013.130
  54. Yang CY, Lin MW, Chang YL, Wu CT, Yang PC. Programmed cell death-ligand 1 expression in surgically resected stage I pulmonary adenocarcinoma and its correlation with driver mutations and clinical outcomes. Eur J Cancer 2014;50:1361-1369. https://doi.org/10.1016/j.ejca.2014.01.018
  55. Schalper KA, Velcheti V, Carvajal D, Wimberly H, Brown J, Pusztai L, et al. In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin Cancer Res 2014;20:2773-2782. https://doi.org/10.1158/1078-0432.CCR-13-2702
  56. Afreen S, Dermime S. The immunoinhibitory B7-H1 molecule as a potential target in cancer: killing many birds with one stone. Hematol Oncol Stem Cell Ther 2014;7:1-17. https://doi.org/10.1016/j.hemonc.2013.09.005
  57. Kim JW, Nam KH, Ahn SH, Park do J, Kim HH, Kim SH, et al. Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer. Gastric Cancer 2016;19:42-52. https://doi.org/10.1007/s10120-014-0440-5

Cited by

  1. Strategies for Bispecific Single Chain Antibody in Cancer Immunotherapy vol.8, pp.18, 2016, https://doi.org/10.7150/jca.19501
  2. Clinical application of a cancer genomic profiling assay to guide precision medicine decisions vol.14, pp.4, 2016, https://doi.org/10.2217/pme-2017-0011
  3. Factors Associated With Host Immune Response and Number of Lymph Nodes: A Large Retrospective Cohort Study vol.25, pp.12, 2018, https://doi.org/10.1245/s10434-018-6731-z
  4. The oncogenic role of Epstein–Barr virus‐encoded micro RNA s in Epstein–Barr virus‐associated gastric carcinoma vol.22, pp.1, 2016, https://doi.org/10.1111/jcmm.13354
  5. A common molecular signature of intestinal-type gastric carcinoma indicates processes related to gastric carcinogenesis vol.9, pp.7, 2016, https://doi.org/10.18632/oncotarget.23670
  6. Immunoclassification characterized by CD8 and PD-L1 expression is associated with the clinical outcome of gastric cancer patients vol.9, pp.15, 2016, https://doi.org/10.18632/oncotarget.24037
  7. Outlooks on Epstein-Barr virus associated gastric cancer vol.66, pp.None, 2016, https://doi.org/10.1016/j.ctrv.2018.03.006
  8. Molecular features and translational outlook for Epstein-Barr virus-associated gastric cancer vol.13, pp.11, 2016, https://doi.org/10.2217/fvl-2018-0071
  9. CMV and EBV targets recognized by tumor-infiltrating B lymphocytes in pancreatic cancer and brain tumors vol.8, pp.None, 2016, https://doi.org/10.1038/s41598-018-34710-2
  10. Epidemiology of gastric cancer: global trends, risk factors and prevention vol.14, pp.1, 2019, https://doi.org/10.5114/pg.2018.80001
  11. Signet ring cell component, not the Lauren subtype, predicts poor survival: an analysis of 198 cases of gastric cancer vol.15, pp.4, 2016, https://doi.org/10.2217/fon-2018-0354
  12. S‐S‐PEG‐COOH Self‐Assembled Monolayer on Gold Surface Enabled a Combined Assay for Serological EBV Antibody Isotypes vol.13, pp.3, 2016, https://doi.org/10.1002/prca.201800067
  13. High Proportion of Potential Candidates for Immunotherapy in a Chilean Cohort of Gastric Cancer Patients: Results of the FORCE1 Study vol.11, pp.9, 2016, https://doi.org/10.3390/cancers11091275
  14. EBV-Positive Gastric Cancer: Current Knowledge and Future Perspectives vol.10, pp.None, 2016, https://doi.org/10.3389/fonc.2020.583463
  15. The Role of Gastric Mucosal Immunity in Gastric Diseases vol.2020, pp.None, 2016, https://doi.org/10.1155/2020/7927054
  16. New Treatment Options for Advanced Gastroesophageal Tumours: Mature for the Current Practice? vol.12, pp.2, 2020, https://doi.org/10.3390/cancers12020301
  17. Potential prognostic impact of EBV RNA‐seq reads in gastric cancer: a reanalysis of The Cancer Genome Atlas cohort vol.10, pp.3, 2016, https://doi.org/10.1002/2211-5463.12803
  18. The impact of EBV on the epigenetics of gastric carcinoma vol.15, pp.3, 2016, https://doi.org/10.2217/fvl-2019-0148
  19. The role of toll-like receptor 9 (TLR9) in Epstein-Barr virus-associated gastric cancer vol.33, pp.2, 2016, https://doi.org/10.2478/cipms-2020-0020
  20. The Role of EBV-Induced Hypermethylation in Gastric Cancer Tumorigenesis vol.12, pp.11, 2020, https://doi.org/10.3390/v12111222
  21. Rapidly Evolving Treatment Landscape for Metastatic Esophagogastric Carcinoma: Review of Recent Data vol.14, pp.None, 2021, https://doi.org/10.2147/ott.s216047
  22. Clinicopathological and Immunomicroenvironment Characteristics of Epstein–Barr Virus-Associated Gastric Cancer in a Chinese Population vol.10, pp.None, 2016, https://doi.org/10.3389/fonc.2020.586752
  23. Identification of anti-Epstein-Barr virus (EBV) antibody signature in EBV-associated gastric carcinoma vol.24, pp.4, 2016, https://doi.org/10.1007/s10120-021-01170-z
  24. TCGA-TCIA-Based CT Radiomics Study for Noninvasively Predicting Epstein-Barr Virus Status in Gastric Cancer vol.217, pp.1, 2016, https://doi.org/10.2214/ajr.20.23534
  25. Molecular Genetics in Epstein-Barr Virus-Associated Malignancies vol.11, pp.7, 2021, https://doi.org/10.3390/life11070593
  26. Recent advances in immune therapies for gastric cancer vol.28, pp.9, 2016, https://doi.org/10.1038/s41417-021-00310-y