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Prognostic significance of circulating CD19+ B lymphocytes in EBV-associated nasopharyngeal carcinoma

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Abstract

In this retrospective study, the correlation between pre- and post-treatment plasma Epstein–Barr virus (EBV) DNA and circulating immune subsets as well as the prognostic implications was investigated in nasopharyngeal carcinoma (NPC) patients. Patients (n = 356) were diagnosed and received comprehensive treatment at the First People’s Hospital of Foshan from 2006 to 2010. Pre- and post-treatment plasma EBV DNA load and circulating immune subsets (percentage of CD3+ T cell, CD3+ CD4+ T cells, CD3+ CD8+ T cells, CD19+ B cells and CD56+ NK cells) were analyzed by real-time PCR and flow cytometry. Patient age correlated negatively with CD3+ T cells (r = −0.264, P = 0.001) and positively with CD56+ NK cells (r = 0.272, P = 0.001). Pre-treatment plasma EBV DNA correlated negatively with CD19+ B cells (r = −0.223, P = 0.009) and CD4/CD8 ratio (r = −0.177, P = 0.047). Patients with low CD19+ B cell had poorer 5-year progression-free survival (PFS) (66.6 vs. 81.8 %, P = 0.036) and 5-year overall survival (OS) (70.5 vs. 81.5 %, P = 0.097) than patients with high CD19+ B cells. Low CD19+ B cells was identified as a negative prognostic factor for 5-year PFS (hazard ratio [HR] 0.487; P = 0.040), but not for 5-year OS (HR 0.550; P = 0.102) in multivariate analysis. Post-treatment plasma EBV DNA was the most important prognostic factor for 5-year PFS (HR 2.983; P = 0.006) and 5-year OS (HR 3.927; P < 0.001). This study demonstrates the clinical value of circulating CD19+ B cell measurements in NPC patients.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. Lee AW, Ng WT, Chan YH, Sze H, Chan C, Lam TH. The battle against nasopharyngeal cancer. Radiother Oncol. 2012;104:272–8.

    Article  PubMed  Google Scholar 

  3. Bensouda Y, Kaikani W, Ahbeddou N, Rahhali R, Jabri M, Mrabti H, Boussen H, Errihani H. Treatment for metastatic nasopharyngeal carcinoma. Eur Ann Otorhinolaryngol Head Neck Dis. 2011;128(2):79–85.

    Article  PubMed  CAS  Google Scholar 

  4. Chan AT. Nasopharyngeal carcinoma. Ann Oncol. 2010;21(Suppl 7):vii308–12.

    PubMed  Google Scholar 

  5. Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, Jiang RS. Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med. 2004;350:2461–70.

    Article  PubMed  CAS  Google Scholar 

  6. Hou X, Chong Zhao, Guo Y, Han F, Lu LX, Wu SX, Li S, Huang PY, Huang H, Zhang L. Different clinical significance of pre- and post-treatment plasma Epstein-Barr virus DNA load in nasopharyngeal carcinoma treated with radiotherapy. Clin Oncol. 2011;23:128–33.

    Article  Google Scholar 

  7. Lin JC, Wang WY, Liang WM, Chou HY, Jan JS, Jiang RS, Wang JY, Twu CW, Liang KL, Chao J, Shen WC. Long-term prognostic effects of plasma Epstein-Barr virus DNA by minor groove binder-probe real-time quantitative PCR on nasopharyngeal carcinoma patients receiving concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2007;68:1342–8.

    Article  PubMed  CAS  Google Scholar 

  8. Wang WY, Twu CW, Chen HH, Jan JS, Jiang RS, Chao JY, Liang KL, Chen KW, Wu CT, Lin JC. Plasma EBV DNA clearance rate as a novel prognostic marker for metastatic/recurrent nasopharyngeal carcinoma. Clin Cancer Res. 2010;16:1016–24.

    Article  PubMed  CAS  Google Scholar 

  9. Leung SF, Chan KC, Ma BB, Hui EP, Mo F, Chow KC, Leung L, Chu KW, Zee B, Lo YM, Chan AT. Plasma Epstein-Barr viral DNA load at midpoint of radiotherapy course predicts outcome in advanced-stage nasopharyngeal carcinoma. Ann Oncol. 2014;25:1204–8.

    Article  PubMed  CAS  Google Scholar 

  10. Straathof KC, Bollard CM, Popat U, Huls MH, Lopez T, Morriss MC, Gresik MV, Gee AP, Russell HV, Brenner MK, Rooney CM, Heslop HE. Treatment of nasopharyngeal carcinoma with Epstein-Barr virus–specific T lymphocytes. Blood. 2005;105:1898–904.

    Article  PubMed  CAS  Google Scholar 

  11. Comoli P, Pedrazzoli P, Maccario R, Basso S, Carminati O, Labirio M, Schiavo R, Secondino S, Frasson C, Perotti C, Moroni M, Locatelli F, Siena S. Cell therapy of stage IV nasopharyngeal carcinoma with autologous Epstein-Barr virus-targeted cytotoxic T lymphocytes. J Clin Oncol. 2005;23:8942–9.

    Article  PubMed  CAS  Google Scholar 

  12. Louis CU, Straathof K, Bollard CM, Ennamuri S, Gerken C, Lopez TT, Huls MH, Sheehan A, Wu MF, Liu H, Gee A, Brenner MK, Rooney CM, Heslop HE, Gottschalk S. Adoptive transfer of EBV-specific T cells results in sustained clinical responses in patients with locoregional nasopharyngeal carcinoma. J Immunother. 2010;33(9):983–90.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Chia WK, Teo M, Wang WW, Lee B, Ang SF, Tai WM, Chee CL, Ng J, Kan R, Lim WT, Tan SH, Ong WS, Cheung YB, Tan EH, Connolly JE, Gottschalk S, Toh HC. Adoptive T cell transfer and chemotherapy in the first-line treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma. Mol Ther. 2014;22:132–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Plonquet A, Haioun C, Jais JP, Debard AL, Salles G, Bene MC, Feugier P, Rabian C, Casasnovas O, Labalette M, Kuhlein E, Farcet JP, Emile JF, Gisselbrecht C, Delfau-Larue MH. Groupe d’étude des lymphomes de l’adulte. Peripheral blood natural killer cell count is associated with clinical outcome in patients with aaIPI 2-3 diffuse large B cell lymphoma. Ann Oncol. 2007;18:1209–15.

    Article  PubMed  CAS  Google Scholar 

  15. Ersvaer E, Hampson P, Wendelbo Ø. Lord JM, Gjertsen BT, Bruserud Ø Circulating T cells in patients with untreated acute myelogenous leukemia are heterogeneous and can be activated through the CD3/TCR complex. Hematology. 2007;12:199–207.

    Article  PubMed  CAS  Google Scholar 

  16. Lau KM, Cheng SH, Lo KW, Lee SA, Woo JK, van Hasselt CA, Lee SP, Rickinson AB, Ng MH. Increase in circulating Foxp3+CD4+CD25 (high) regulatory T cells in nasopharyngeal carcinoma patients. Br J Cancer. 2007;96:617–22.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Hsu MC, Hsiao JR, Chang KC, Wu YH, Su IJ, Jin YT, Chang Y. Increase of programmed death-1-expressing intratumoral CD8 T cells predicts a poor prognosis for nasopharyngeal carcinoma. Mod Pathol. 2010;23:1393–403.

    Article  PubMed  CAS  Google Scholar 

  18. Wei WH, Cai XY, Xu T, Zhang GY, Wu YF, Feng WN, Lin L, Deng YM, Lu QX, Huang ZL. Concurrent weekly docetaxel chemotherapy in combination with radiotherapy for stage III and IVA-B nasopharyngeal carcinoma. Asian Pac J Cancer Prev. 2012;13:785–9.

    Article  PubMed  Google Scholar 

  19. Wei W, Huang Z, Li S, Chen H, Zhang G, Li S, Hu W, Xu T. Pre-treatment Epstein-Barr Virus DNA load and cumulative cisplatin dose intensity affect long-term outcome of nasopharyngeal carcinoma treated with concurrent chemotherapy: experience of an Institute in an Endemic Area. Oncol Res Treat. 2014;37:88–95.

    Article  PubMed  CAS  Google Scholar 

  20. Cohen JI. Epstein-Barr virus infection. N Engl J Med. 2000;343:481–92.

    Article  PubMed  CAS  Google Scholar 

  21. Kurth J, Spieker T, Wustrow J, Strickler GJ, Hansmann LM, Rajewsky K, Küppers R. EBV-infected B cells in infectious mononucleosis: viral strategies for spreading in the B cell compartment and establishing latency. Immunity. 2000;13:485–95.

    Article  PubMed  CAS  Google Scholar 

  22. Ressing ME, Horst D, Griffin BD, Tellam J, Zuo J, Khanna R, Rowe M, Wiertz EJ. Epstein-Barr virus evasion of CD8(+) and CD4(+) T cell immunity via concerted actions of multiple gene products. Semin Cancer Biol. 2008;18:397–408.

    Article  PubMed  CAS  Google Scholar 

  23. Hatton OL, Harris-Arnold A, Schaffert S, Krams SM, Martinez OM. The interplay between Epstein-Barr virus and B lymphocytes: implications for infection, immunity, and disease. Immunol Res. 2014;58:268–76.

    Article  PubMed  CAS  Google Scholar 

  24. Qin Z, Blankenstein T. CD4+ T cell-mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFNg receptor expression by nonhematopoietic cells. Immunity. 2000;12:677–86.

    Article  PubMed  CAS  Google Scholar 

  25. Ossendorp F, Toes RE, Offringa R, van der Burg SH, Melief CJ. Importance of CD4(+) T helper cell responses in tumor immunity. Immunol Lett. 2000;74:75–9.

    Article  PubMed  CAS  Google Scholar 

  26. Gerloni M, Zanetti M. CD4 T cells in tumor immunity. Springer Semin Immunopathol. 2005;27:37–48.

    Article  PubMed  CAS  Google Scholar 

  27. Péron J, Cropet C, Tredan O, Bachelot T, Bachelot T, Ray-Coquard I, Clapisson G, Chabaud S, Philip I, Borg C, Cassier P, Labidi Galy I, Sebban C, Perol D, Biron P, Caux C, Menetrier-Caux C, Blay JY. CD4 lymphopenia to identify end-of-life metastatic cancer patients. Eur J Cancer. 2013;49:1080–9.

    Article  PubMed  Google Scholar 

  28. Trédan O, Manuel M, Clapisson G, Bachelot T, Chabaud S, Bardin-dit-Courageot C, Rigal C, Biota C, Bajard A, Pasqual N, Blay JY, Caux C, Ménétrier-Caux C. Patients with metastatic breast cancer leading to CD4+ T cell lymphopenia have poor outcome. Eur J Cancer. 2013;49:1673–82.

    Article  PubMed  Google Scholar 

  29. Buggert M, Frederiksen J, Noyan K, Svärd J, Barqasho B, Sönnerborg A, Lund O, Nowak P, Karlsson AC. Multiparametric bioinformatics distinguish the CD4/CD8 ratio as a suitable laboratory predictor of combined T cell pathogenesis in HIV infection. J Immunol. 2014;192:2099–108.

    Article  PubMed  CAS  Google Scholar 

  30. Pretscher D, Distel LV, Grabenbauer GG, Wittlinger M, Buettner M, Niedobitek G. Distribution of immune cells in head and neck cancer: CD8+ T cells and CD20+ B cells in metastatic lymph nodes are associated with favourable outcome in patients with oro- and hypopharyngeal carcinoma. BMC Cancer. 2009;9:292.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Iriyama N, Hatta Y, Takeuchi J, Ogawa Y, Ohtake S, Sakura T, Mitani K, Ishida F, Takahashi M, Maeda T, Izumi T, Sakamaki H, Miyawaki S, Honda S, Miyazaki Y, Taki T, Taniwaki M, Naoe T. CD56 expression is an independent prognostic factor for relapse in acute myeloid leukemia with t(8;21). Leuk Res. 2013;37:1021–6.

    Article  PubMed  CAS  Google Scholar 

  32. Plonquet A, Haioun C, Jais JP, Debard AL, Salles G, Bene MC, Feugier P, Rabian C, Casasnovas O, Labalette M, Kuhlein E, Farcet JP, Emile JF, Gisselbrecht C, Delfau-Larue MH. Groupe d’étude des lymphomes de l’adulte. Peripheral blood natural killer cell count is associated with clinical outcome in patients with aaIPI 2-3 diffuse large B cell lymphoma. Ann Oncol. 2007;18:1209–15.

    Article  PubMed  CAS  Google Scholar 

  33. Yip TT, Ngan RK, Fong AH, Law SC. Application of circulating plasma/serum EBV DNA in the clinical management of nasopharyngeal carcinoma. Oral Oncol. 2014;50:527–38.

    Article  PubMed  CAS  Google Scholar 

  34. Fogg M. Murphy JR, Lorch J, Posner M, Wang F Therapeutic targeting of regulatory T cells enhances tumor-specific CD8+ T cell responses in Epstein-Barr virus associated nasopharyngeal carcinoma. Virology. 2013;441:107–13.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Yang CF, Peng LX, Huang TJ, Yang GD, Chu QQ, Liang YY, Cao X, Xie P, Zheng LS, Huang HB, Cai MD, Huang JL, Liu RY, Zhu ZY, Qian CN, Huang BJ. Cancer stem-like cell characteristics induced by EB virus-encoded LMP1 contribute to radioresistance in nasopharyngeal carcinoma by suppressing the p53-mediated apoptosis pathway. Cancer Lett. 2014;344:260–71.

    Article  PubMed  CAS  Google Scholar 

  36. Hu FJ, Ge MH, Li P, Wang CC, Ling YT, Mao WM, Ling ZQ. Unfavorable clinical implications of circulating CD44+ lymphocytes in patients with nasopharyngeal carcinoma undergoing radiochemotherapy. Clin Chim Acta. 2012;413:213–8.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by Grants from the National Natural Science Foundation of China (81372410, 81071837, 30670627), the Scientific and Technological Project of Guangdong, China (2010B050700016, 9251008, 901000005, 06021210 to YHL, 2010B031600086 to HWH) and the Natural Science Foundation of Guangdong Province, P. R. China, (9151008901000223 to HWH).

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Correspondence to Tao Xu, Huiling Yang or Weihan Hu.

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Xu, T., Huang, Z., Su, B. et al. Prognostic significance of circulating CD19+ B lymphocytes in EBV-associated nasopharyngeal carcinoma. Med Oncol 31, 198 (2014). https://doi.org/10.1007/s12032-014-0198-y

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