DOI QR코드

DOI QR Code

Expression of Epstein-Barr Virus Gene and Clonality of Infiltrated T Lymphocytes in Epstein-Barr Virus-associated Gastric Carcinoma

  • Lee, Jae-Myun (Department of Microbiology, Brain Korea Project 21 of Medical Sciences, Institute for Immunology and Immunological Diseases) ;
  • Kim, Ho-Guen (Department of Pathology, Yonsei University College of Medicine) ;
  • Noh, Sung-Hoon (Department of Surgery, Yonsei University College of Medicine) ;
  • Lee, Won-Young (Department of Microbiology, Brain Korea Project 21 of Medical Sciences, Institute for Immunology and Immunological Diseases) ;
  • Kim, Se-Jong (Department of Microbiology, Brain Korea Project 21 of Medical Sciences, Institute for Immunology and Immunological Diseases) ;
  • Park, Jeon-Han (Department of Microbiology, Brain Korea Project 21 of Medical Sciences, Institute for Immunology and Immunological Diseases)
  • Received : 2010.12.27
  • Accepted : 2011.01.10
  • Published : 2011.02.28

Abstract

Background: Epstein-Barr virus associated gastric lymphoepithelioma-like carcinoma (LELC) is characterized by the intensive infiltration of lymphoid cells, the presence of EBV, and the better prognosis over typical adenocarcinoma. Thus, it was assumable that viral latent proteins may be responsible for the recruitment of a certain T cell repertoire to EBV-associated gastric carcinoma. Methods: To examine above possibility, EBV gene expression in gastric carcinoma tissues and usage of TCR among the tumor infiltrating lymphocytes were analyzed. Results: EBV specific DNA and EBERs RNA were detected in 4 out of 30 patients. RT-PCR analysis revealed that all 4 of EBV-positive tumor tissues expressed EBNA1 mRNA and BARTs and LMP2a was detected only one sample out of 4. However, the EBNA2 and LMP-1 transcripts were not detected in these tissues. $CD8^+$ T cells were the predominant population of infiltrating lymphocytes in the EBV-positive gastric carcinoma. According to spectra type analysis of infiltrating T cells, 10 predominant bands were detected by TCR $V{\beta}$ CDR3 specific RT-PCR from 4 EBV-positive tumor tissues. Sequence analysis of these bands revealed oligoclonal expansion of T cells. Conclusion: These findings suggest that clonally expanded T cells in vivo might be a population of cytotoxic T cells reactive to EBV-associated gastric carcinoma.

References

  1. Rickinson AB, Kieff E. Epstein-Barr virus. In: Knipe DM, Howley PM, editors. Fields virology. 5th ed. Philadelphia: Lippincott Williams & Wilkins; p2655-2700, 2007
  2. Kieff E, Rickinson AB. Epstein-Barr Virus and its replication. In: Fields BN, Knipe DM, Howley PM, editors. Fields Virology. 5th ed. Philadelphia: Lippincott-Williams & Wilkins Publishers; p2603-2654, 2007
  3. Sample J, Brooks L, Sample C, Young L, Rowe M, Gregory C, Rickinson A, Kieff E: Restricted Epstein-Barr virus protein expression in Burkitt lymphoma is due to a different Epstein-Barr nuclear antigen 1 transcriptional initiation site. Proc Natl Acad Sci U S A 88;6343-6347, 1991 https://doi.org/10.1073/pnas.88.14.6343
  4. Young LS, Murray PG: Epstein-Barr virus and oncogenesis: from latent genes to tumours. Oncogene 22;5108-5121, 2003 https://doi.org/10.1038/sj.onc.1206556
  5. Boon T, van der Bruggen P: Human tumor antigens recognized by T lymphocytes. J Exp Med 183;725-729, 1996
  6. Rickinson AB, Moss DJ: Human cytotoxic T lymphocyte responses to Epstein-Barr virus infection. Annu Rev Immunol 15;405-431, 1997 https://doi.org/10.1146/annurev.immunol.15.1.405
  7. Kienzle N, Sculley TB, Poulsen L, Buck M, Cross S, Raab-Traub N, Khanna R: Identification of a cytotoxic T-lymphocyte response to the novel BARF0 protein of Epstein-Barr virus: a critical role for antigen expression. J Virol 72;6614-6620, 1998
  8. Blake N, Lee S, Redchenko I, Thomas W, Steven N, Leese A, Steigerwald-Mullen P, Kurilla MG, Frappier L, Rickinson A: Human CD8+ T cell responses to EBV EBNA1: HLA class I presentation of the (Gly-Ala)-containing protein requires exogenous processing. Immunity 7;791-802, 1997 https://doi.org/10.1016/S1074-7613(00)80397-0
  9. Yin Y, Manoury B, Fahraeus R: Self-inhibition of synthesis and antigen presentation by Epstein-Barr virus-encoded EBNA1. Science 301;1371-1374, 2003 https://doi.org/10.1126/science.1088902
  10. Akiba S, Koriyama C, Herrera-Goepfert R, Eizuru Y: Epstein- Barr virus associated gastric carcinoma: epidemiological and clinicopathological features. Cancer Sci 99;195-201, 2008 https://doi.org/10.1111/j.1349-7006.2007.00674.x
  11. Burke AP, Yen TS, Shekitka KM, Sobin LH: Lymphoepithelial carcinoma of the stomach with Epstein-Barr virus demonstrated by polymerase chain reaction. Mod Pathol 3;377-380, 1990
  12. Herath CH, Chetty R: Epstein-Barr virus-associated lymphoepithelioma- like gastric carcinoma. Arch Pathol Lab Med 132;706-709, 2008
  13. 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 73;2239-2249, 1994 https://doi.org/10.1002/1097-0142(19940501)73:9<2239::AID-CNCR2820730902>3.0.CO;2-#
  14. Corvalan A, Ding S, Koriyama C, Carrascal E, Carrasquilla G, Backhouse C, Urzua L, Argandona J, Palma M, Eizuru Y, Akiba S: Association of a distinctive strain of Epstein-Barr virus with gastric cancer. Int J Cancer 118;1736-1742, 2006 https://doi.org/10.1002/ijc.21530
  15. Minamoto T, Mai M, Watanabe K, Ooi A, Kitamura T, Takahashi Y, Ueda H, Ogino T, Nakanishi I: 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 66;945-952, 1990 https://doi.org/10.1002/1097-0142(19900901)66:5<945::AID-CNCR2820660523>3.0.CO;2-X
  16. van Beek J, zur Hausen A, Snel SN, Berkhof J, Kranenbarg EK, van de Velde CJ, van den Brule AJ, Middeldorp JM, Meijer CJ, Bloemena E: Morphological evidence of an activated cytotoxic T-cell infiltrate in EBV-positive gastric carcinoma preventing lymph node metastases. Am J Surg Pathol 30;59-65, 2006 https://doi.org/10.1097/01.pas.0000176428.06629.1e
  17. Sample J, Young L, Martin B, Chatman T, Kieff E, Rickinson A, Kieff E: Epstein-Barr virus types 1 and 2 differ in their EBNA-3A, EBNA-3B, and EBNA-3C genes. J Virol 64;4084- 4092, 1990
  18. Sugiura M, Imai S, Tokunaga M, Koizumi S, Uchizawa M, Okamoto K, Osato T: Transcriptional analysis of Epstein- Barr virus gene expression in EBV-positive gastric carcinoma: unique viral latency in the tumour cells. Br J Cancer 74;625-631, 1996 https://doi.org/10.1038/bjc.1996.412
  19. Choi IH, Chwae YJ, Shim WS, Kim DS, Kwon DH, Kim JD, Kim SJ: Clonal expansion of CD8+ T cells in Kawasaki disease. J Immunol 159;481-486, 1997
  20. Hall BL, Finn OJ: PCR-based analysis of the T-cell receptor V beta multigene family: experimental parameters affecting its validity. Biotechniques 13;248-257, 1992
  21. Shibata D, Weiss LM: Epstein-Barr virus-associated gastric adenocarcinoma. Am J Pathol 140;769-774, 1992
  22. Takada K: Epstein-Barr virus and gastric carcinoma. Mol Pathol 53;255-261, 2000 https://doi.org/10.1136/mp.53.5.255
  23. 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 27;20-27, 1996 https://doi.org/10.1016/S0046-8177(96)90133-1
  24. van Beek J, zur Hausen A, Klein Kranenbarg E, van de Velde CJ, Middeldorp JM, van den Brule AJ, Meijer CJ, Bloemena E: EBV-positive gastric adenocarcinomas: a distinct clinicopathologic entity with a low frequency of lymph node involvement. J Clin Oncol 22;664-670, 2004 https://doi.org/10.1200/JCO.2004.08.061
  25. Imai S, Koizumi S, Sugiura M, Tokunaga M, Uemura Y, Yamamoto N, Tanaka S, Sato E, Osato T: Gastric carcinoma: monoclonal epithelial malignant cells expressing Epstein- Barr virus latent infection protein. Proc Natl Acad Sci U S A 91;9131-9135, 1994 https://doi.org/10.1073/pnas.91.19.9131
  26. Shin WS, Kang MW, Kang JH, Choi MK, Ahn BM, Kim JK, Sun HS, Min KW: Epstein-Barr virus-associated gastric adenocarcinomas among Koreans. Am J Clin Pathol 105;174- 181, 1996 https://doi.org/10.1093/ajcp/105.2.174
  27. Sixbey JW, Shirley P, Chesney PJ, Buntin DM, Resnick L: Detection of a second widespread strain of Epstein-Barr virus. Lancet 2;761-765, 1989
  28. Fukayama M: Epstein-Barr virus and gastric carcinoma. Pathol Int 60;337-350, 2010 https://doi.org/10.1111/j.1440-1827.2010.02533.x
  29. Steven NM, Annels NE, Kumar A, Leese AM, Kurilla MG, Rickinson AB: Immediate early and early lytic cycle proteins are frequent targets of the Epstein-Barr virus-induced cytotoxic T cell response. J Exp Med 185;1605-1617, 1997 https://doi.org/10.1084/jem.185.9.1605
  30. Levitskaya J, Coram M, Levitsky V, Imreh S, Steigerwald- Mullen PM, Klein G, Kurilla MG, Masucci MG: Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature 375;685-688, 1995 https://doi.org/10.1038/375685a0
  31. Munz C, Bickham KL, Subklewe M, Tsang ML, Chahroudi A, Kurilla MG, Zhang D, O'Donnell M, Steinman RM: Human CD4(+) T lymphocytes consistently respond to the latent Epstein-Barr virus nuclear antigen EBNA1. J Exp Med 191;1649-1660, 2000 https://doi.org/10.1084/jem.191.10.1649
  32. Roskrow MA, Suzuki N, Gan Y, Sixbey JW, Ng CY, Kimbrough S, Hudson M, Brenner MK, Heslop HE, Rooney CM: Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for the treatment of patients with EBV-positive relapsed Hodgkin's disease. Blood 91;2925-2934, 1998