Advertisement

Medical Oncology

, 32:86 | Cite as

Co-expression of PD-1 and PD-L1 predicts poor outcome in nasopharyngeal carcinoma

  • Jianwei Zhang
  • Wenfeng Fang
  • Tao Qin
  • Yunpeng Yang
  • Shaodong Hong
  • Wenhua Liang
  • Yuxiang Ma
  • Hongyun Zhao
  • Yan Huang
  • Cong Xue
  • Peiyu Huang
  • Zhihuang Hu
  • Yuanyuan Zhao
  • Li Zhang
Original Paper

Abstract

Tumor immune evasion is a hallmark of cancer. The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway has been suggested to play an important role in T cell tolerance and tumor immune escape. In this study, we aimed to evaluate the correlation between the expression of PD-1/PD-L1 and the post-treatment outcome in patients with nasopharyngeal carcinoma (NPC). Formalin-fixed, paraffin-embedded tissue biopsies from 139 patients with histological diagnosis of NPC treated with conventional chemoradiotherapy were studied. By using immunohistochemistry staining, expressions of PD-1 on tumor-infiltrating lymphocyte and PD-L1 on tumor tissue were detected. The staining results were evaluated with H-score. The correlation between PD-1/PD-L1 expression and clinical characteristics and post-treatment outcome were analyzed. PD-1+ immune cell were present in 52 of these 139 tumors (37.4 %). PD-L1 expression was detected in 132 patients (95.0 %), which located on tumor tissue. High expression of PD-L1 (median H-score >35) in tumor tissue significantly correlated with a poor prognosis of disease-free survival (P = 0.009). Co-expression of PD-1 and PD-L1 in NPC at diagnosis correlated with the poorest prognosis of disease-free survival (P = 0.038). PD-1/PD-L1 co-expression reflected the selective suppression of cytotoxic lymphocytes in the tumor microenvironment and predicted recurrence and metastasis of NPC after conventional therapies. Blocking this pathway in patients with co-expression of PD-1/PD-L1 provides a potential therapy target for NPC.

Keywords

PD-1/PD-L1 Nasopharyngeal carcinoma Immunohistochemistry Prognosis 

Notes

Acknowledgments

This work was supported by grants from the the National High Technology Research and Development Program of China (863 Program No. 2012AA02A501 and 2012AA02A502), the Natural Science Foundation of Guangdong (Grant No. S2013010016564). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

All authors declared no conflict of interest.

References

  1. 1.
    Chan AT, Teo PM, Johnson PJ. Nasopharyngeal cancer. Cancer Treat Res. 2003;114:275–93.CrossRefPubMedGoogle Scholar
  2. 2.
    Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMedGoogle Scholar
  3. 3.
    Cao SM, Simons MJ, Qian CN. The prevalence and prevention of nasopharyngeal carcinoma in China. Chin J Cancer. 2011;30:114–9.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Ma BB, Hui EP, Chan AT. Systemic approach to improving treatment outcome in nasopharyngeal carcinoma: current and future directions. Cancer Sci. 2008;99:1311–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Xiao WW, Huang SM, Han F, et al. Local control, survival, and late toxicities of locally advanced nasopharyngeal carcinoma treated by simultaneous modulated accelerated radiotherapy combined with cisplatin concurrent chemotherapy: long-term results of a phase 2 study. Cancer. 2011;117:1874–83.CrossRefPubMedGoogle Scholar
  6. 6.
    Shanmugaratnam K, Sobin LH. The World Health Organization histological classification of tumours of the upper respiratory tract and ear. A commentary on the second edition. Cancer. 1993;71:2689–97.CrossRefPubMedGoogle Scholar
  7. 7.
    Khanna R, Busson P, Burrows SR, et al. Molecular characterization of antigen-processing function in nasopharyngeal carcinoma (NPC): evidence for efficient presentation of Epstein-Barr virus cytotoxic T-cell epitopes by NPC cells. Cancer Res. 1998;58:310–4.PubMedGoogle Scholar
  8. 8.
    Lin X, Gudgeon NH, Hui EP, et al. CD4 and CD8 T cell responses to tumour-associated Epstein-Barr virus antigens in nasopharyngeal carcinoma patients. Cancer Immunol Immunother. 2008;57:963–75.CrossRefPubMedGoogle Scholar
  9. 9.
    Li J, Zeng XH, Mo HY, et al. Functional inactivation of EBV-specific T-lymphocytes in nasopharyngeal carcinoma: implications for tumor immunotherapy. PLoS One. 2007;2:e1122.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy–inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.CrossRefPubMedGoogle Scholar
  12. 12.
    Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res. 2013;19:1021–34.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–34.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443:350–4.CrossRefPubMedGoogle Scholar
  18. 18.
    Urbani S, Amadei B, Tola D, et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol. 2006;80:11398–403.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Muenst S, Hoeller S, Dirnhofer S, Tzankov A. Increased programmed death-1 + tumor-infiltrating lymphocytes in classical Hodgkin lymphoma substantiate reduced overall survival. Hum Pathol. 2009;40:1715–22.CrossRefPubMedGoogle Scholar
  20. 20.
    Thompson RH, Dong H, Lohse CM, et al. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res. 2007;13:1757–61.CrossRefPubMedGoogle Scholar
  21. 21.
    Zeng Z, Shi F, Zhou L, 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.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 2013;19:3462–73.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Hsu MC, Hsiao JR, Chang KC, et al. Increase of programmed death-1-expressing intratumoral CD8 T cells predicts a poor prognosis for nasopharyngeal carcinoma. Mod Pathol. 2010;23:1393–403.CrossRefPubMedGoogle Scholar
  24. 24.
    Badoual C, Hans S, Merillon N, et al. PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. 2013;73:128–38.CrossRefPubMedGoogle Scholar
  25. 25.
    Carreras J, Lopez-Guillermo A, Roncador G, et al. High numbers of tumor-infiltrating programmed cell death 1-positive regulatory lymphocytes are associated with improved overall survival in follicular lymphoma. J Clin Oncol. 2009;27:1470–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Fang W, Zhang J, Hong S et al. EBV-driven LMP1 and IFN-gamma up-regulate PD-L1 in nasopharyngeal carcinoma: implications for oncotargeted therapy. Oncotarget. 2014;5(23):12189–202.PubMedCentralPubMedGoogle Scholar
  27. 27.
    Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res. 2004;10:7252–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Pathmanathan R, Prasad U, Sadler R, et al. Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl J Med. 1995;333:693–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209:201–9.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol. 2001;22:265–8.CrossRefPubMedGoogle Scholar
  33. 33.
    Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 2013;19:3462–73.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Thompson RH, Dong H, Kwon ED. Implications of B7-H1 expression in clear cell carcinoma of the kidney for prognostication and therapy. Clin Cancer Res. 2007;13:709s–15s.CrossRefPubMedGoogle Scholar
  35. 35.
    Shi F, Shi M, Zeng Z, et al. PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer. 2011;128:887–96.CrossRefPubMedGoogle Scholar
  36. 36.
    Ghebeh H, Tulbah A, Mohammed S, et al. Expression of B7-H1 in breast cancer patients is strongly associated with high proliferative Ki-67-expressing tumor cells. Int J Cancer. 2007;121:751–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Muenst S, Soysal SD, Gao F, et al. The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 2013;139:667–76.CrossRefPubMedGoogle Scholar
  38. 38.
    Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012;18:1611–8.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Jianwei Zhang
    • 1
    • 2
  • Wenfeng Fang
    • 1
    • 3
  • Tao Qin
    • 1
    • 3
  • Yunpeng Yang
    • 1
    • 3
  • Shaodong Hong
    • 1
    • 3
  • Wenhua Liang
    • 1
    • 3
  • Yuxiang Ma
    • 1
    • 3
  • Hongyun Zhao
    • 1
    • 3
  • Yan Huang
    • 1
    • 3
  • Cong Xue
    • 1
    • 3
  • Peiyu Huang
    • 1
    • 4
  • Zhihuang Hu
    • 1
    • 3
  • Yuanyuan Zhao
    • 1
    • 3
  • Li Zhang
    • 1
    • 3
  1. 1.Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouPeople’s Republic of China
  2. 2.Department of Medical OncologyThe Sixth Affiliated Hospital of Sun Yat-sen UniversityGuangzhouPeople’s Republic of China
  3. 3.Department of Medical Oncology, Sun Yat-sen University Cancer CenterGuangzhouPeople’s Republic of China
  4. 4.Department of Nasopharyngeal CarcinomaSun Yat-sen University Cancer CenterGuangzhouPeople’s Republic of China

Personalised recommendations