Tumor Biology

, Volume 37, Issue 6, pp 7507–7514 | Cite as

Programmed death 1 expression in the peritumoral microenvironment is associated with a poorer prognosis in classical Hodgkin lymphoma

  • Young Wha Koh
  • Yoon Kyung Jeon
  • Dok Hyun Yoon
  • Cheolwon Suh
  • Jooryung Huh
Original Article

Abstract

Programmed cell death protein-1 (PD-1) inhibitor may be therapeutic in patients with relapsed or refractory classical Hodgkin’s lymphoma (cHL). This study examined the prognostic significance of PD-1 and two PD-1 ligands (PD-L1 and PD-L2) in uniformly treated cHL. Diagnostic tissues from 109 cHL patients treated with a doxorubicin, bleomycin, vinblastine, and dacarbazine regimen were evaluated retrospectively by immunohistochemical analysis of PD-L1, PD-L2, and PD-1 expressions. The median follow-up time was 4.91 years (range, 0.17–17.33 years). Thirteen patients (11 %) expressed PD-1 protein in the peritumoral microenvironment, which was associated with poor overall survival (OS) (P = 0.017). PD-L1 or PD-L2 expression was not associated with OS. There was no correlation between PD-L1 and PD-1 expression or between PD-L2 and PD-1 expression. Multivariate analysis identified PD-1 protein as an independent prognostic factor for OS (P = 0.019). Subgroup analysis according to the Ann Arbor stage of cHL showed that PD-1 protein expression had a prognostic value in limited-stage cHL (P = 0.048). PD-1 is an independent prognostic factor in cHL and may allow the identification of a subgroup of patients with limited-stage cHL who require more intensive therapy and who may benefit from anti-PD-1 agents.

Keywords

Hodgkin’s lymphoma PD-L1 PD-L2 PD-1 Prognosis 

Supplementary material

13277_2015_4622_MOESM1_ESM.docx (17 kb)
ESM 1(DOCX 17 kb)

References

  1. 1.
    Bjorkholm M, Axdorph U, Grimfors G, Merk K, Johansson B, Landgren O, et al. Fixed versus response-adapted MOPP/ABVD chemotherapy in Hodgkin’s disease. A prospective randomized trial. Annals Oncol. 1995;6:895–9.Google Scholar
  2. 2.
    Quddus F, Armitage JO. Salvage therapy for Hodgkin’s lymphoma. Cancer J. 2009;15:161–3.CrossRefPubMedGoogle Scholar
  3. 3.
    Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International prognostic factors project on advanced Hodgkin’s disease. N Engl J Med. 1998;339:1506–14.CrossRefPubMedGoogle Scholar
  4. 4.
    Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19:813–24.CrossRefPubMedGoogle Scholar
  6. 6.
    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
  7. 7.
    Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010;37:430–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Bertucci F, Finetti P, Mamessier E, Pantaleo MA, Astolfi A, Ostrowski J, et al. PDL1 expression is an independent prognostic factor in localized gist. Oncoimmunology. 2015;4:e1002729.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Zhang J, Fang W, Qin T, Yang Y, Hong S, Liang W, et al. Co-expression of PD-1 and PD-L1 predicts poor outcome in nasopharyngeal carcinoma. Med Oncol. 2015;32:86.CrossRefPubMedGoogle Scholar
  10. 10.
    Bellmunt J, Mullane SA, Werner L, Fay AP, Callea M, Leow JJ, et al. Association of PD-L1 expression on tumor-infiltrating mononuclear cells and overall survival in patients with urothelial carcinoma. Ann Oncol. 2015;26:812–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Muenst S, Schaerli AR, Gao F, Daster S, Trella E, Droeser RA, et al. Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 2014;146:15–24.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Zhang Y, Wang L, Li Y, Pan Y, Wang R, Hu H, et al. Protein expression of programmed death 1 ligand 1 and ligand 2 independently predict poor prognosis in surgically resected lung adenocarcinoma. OncoTargets Ther. 2014;7:567–73.CrossRefGoogle Scholar
  13. 13.
    Droeser RA, Hirt C, Viehl CT, Frey DM, Nebiker C, Huber X, et al. Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer. 2013;49:2233–42.CrossRefPubMedGoogle Scholar
  14. 14.
    Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Paydas S, Bagir E, Seydaoglu G, Ercolak V, Ergin M (2015) Programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and EBV-encoded RNA (EBER) expression in Hodgkin lymphoma. Ann HematolGoogle Scholar
  16. 16.
    Rozali EN, Hato SV, Robinson BW, Lake RA, Lesterhuis WJ. Programmed death ligand 2 in cancer-induced immune suppression. Clin Dev Immunol. 2012;2012:656340.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Huh J, Cho K, Heo DS, Kim JE, Kim CW. Detection of Epstein-Barr virus in Korean peripheral T-cell lymphoma. Am J Hematol. 1999;60:205–14.CrossRefPubMedGoogle Scholar
  18. 18.
    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
  19. 19.
    Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, et al. A review of human carcinogens--part b: biological agents. Lancet Oncol. 2009;10:321–2.CrossRefPubMedGoogle Scholar
  20. 20.
    Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27:111–22.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Park JJ, Omiya R, Matsumura Y, Sakoda Y, Kuramasu A, Augustine MM, et al. B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood. 2010;116:1291–8.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012;209:1201–17.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. Pd-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004;574:37–41.CrossRefPubMedGoogle Scholar
  24. 24.
    Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C, Eichbaum Q, et al. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med. 2010;16:1147–51.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med. 2010;16:452–9.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206:3015–29.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015;6:6692.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Brahmer JR, Rizvi NA, Lutzky J (2014b) Clinical activity and biomarkers of MEDI4736, an anti-PD-L1 antibody, in patients with NSCLC. ASCO Meet Abstr 32:8021Google Scholar
  30. 30.
    Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515:558–62.CrossRefPubMedGoogle Scholar
  31. 31.
    Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32:1020–30.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.CrossRefPubMedGoogle Scholar
  33. 33.
    Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384:1109–17.CrossRefPubMedGoogle Scholar
  34. 34.
    Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–35.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–28.CrossRefPubMedGoogle Scholar
  36. 36.
    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Gettinger SN, Shepherd FA, Antonia SJ. First-line nivolumab (anti-PD-1; BMS-936558, ONO-4538) monotherapy in advanced NSCLC: safety, efficacy, and correlation of outcomes with PD-L1 status. ASCO Meet Abstr. 2014;32:8024.Google Scholar
  38. 38.
    Gandhi L (2014) MK-3475 (anti-PD-1 monoclonal antibody) for non-small cell lung cancer (NSCLC): antitumor activity and association with tumor PD-L1 expression [abstract]. Proc Ann Meet AACR CT105Google Scholar
  39. 39.
    Sunshine J, Taube JM. PD-1/PD-L1 inhibitors. Curr Opin Pharmacol. 2015;23:32.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Young Wha Koh
    • 1
  • Yoon Kyung Jeon
    • 2
  • Dok Hyun Yoon
    • 3
  • Cheolwon Suh
    • 3
  • Jooryung Huh
    • 4
  1. 1.Department of PathologyAjou University School of MedicineSuwonSouth Korea
  2. 2.Department of PathologySeoul National University HospitalSeoulSouth Korea
  3. 3.Department of Oncology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulSouth Korea
  4. 4.Department of Pathology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulSouth Korea

Personalised recommendations