Cancer Immunology, Immunotherapy

, Volume 66, Issue 6, pp 777–786 | Cite as

Expression patterns of programmed death-ligand 1 in esophageal adenocarcinomas: comparison between primary tumors and metastases

  • Bastian Dislich
  • Alexandra Stein
  • Christian A. Seiler
  • Dino Kröll
  • Sabina Berezowska
  • Inti Zlobec
  • José Galvan
  • Julia Slotta-Huspenina
  • Axel Walch
  • Rupert LangerEmail author
Original Article


Expression analysis of programmed death-ligand 1 (PD-L1) may be helpful in guiding clinical decisions for immune checkpoint inhibition therapy, but testing by immunohistochemistry may be hampered by heterogeneous staining patterns within tumors and expression changes during metastatic course. PD-L1 expression (clone SP142) was investigated in esophageal adenocarcinomas using tissue microarrays (TMA) from 112 primary resected tumors, preoperative biopsies and full slide sections from a subset of these cases (n = 24), corresponding lymph node (n = 55) and distant metastases (n = 17). PD-L1 expression was scored as 0.1–1, >1, >5, >50% positive membranous staining of tumor cells and any positive staining of tumor-associated inflammatory infiltrates and/or stroma cells. There was a significant correlation with overall PD-L1 expression between the full slide sections and the TMA (p = 0.001), but not with the corresponding biopsies. PD-L1 expression in tumor cells >1% was detected in 8.0% of cases (9/112) and 51.8% of cases (58/112) in tumor-associated inflammatory infiltrates and/or stroma cells of primary tumors. Epithelial expression in metastases was found in 5.6% of cases (4/72) and immune cell expression in 18.1% of cases (13/72), but did not correlate with the expression pattern in the primary tumor. Overall PD-L1 expression in the primary tumor did not influence survival. However, PD-L1 expression was correlated with the number of CD3+ tumor-infiltrating lymphocytes in the tumor center, and a combinational score of PD-L1 status/CD3+ tumor-infiltrating lymphocytes was correlated with patients’ overall survival.


PD-L1 Immunohistochemistry Esophageal adenocarcinoma Metastases 



Esophageal adenocarcinoma


Mismatch repair


Programmed cell death protein 1


Programmed death-ligand 1


Tumor-associated inflammatory infiltrates and/or stroma cells


Tumor cells


Tumor-infiltrating lymphocytes


Tissue microarray



No particular funding source was used for this study.

Author contributions

B. Dislich and R. Langer performed the data analysis and wrote the paper. A. Stein, I. Zlobec and J. Galvan performed data analysis. C. A. Seiler, D. Kröll, S. Berezowska, J. Slotta-Huspenina and A. Walch contributed to data acquisition.

Compliance with ethical standards

Conflict of interest

R. Langer received advisory board honoraria from Bristol-Myers Squibb. S. Berezowska received advisory board honoraria from Merck Sharp & Dohme Corp. and consultation honoraria from Roche. There is no conflict of interest for the other authors of this study.

Supplementary material

262_2017_1982_MOESM1_ESM.pdf (2.8 mb)
Supplementary material 1 (PDF 2821 KB)


  1. 1.
    Napier KJ, Scheerer M, Misra S (2014) Esophageal cancer: a review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol 6(5):112–120. doi: 10.4251/wjgo.v6.i5.112 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Elimova E, Wadhwa R, Shiozaki H, Sudo K, Estrella JS, Badgwell BD, Das P, Matamoros A Jr, Song S, Ajani JA (2015) Molecular biomarkers in gastric cancer. J Natl Compr Cancer Netw 13(4):e19–e29CrossRefGoogle Scholar
  3. 3.
    Lote H, Cafferkey C, Chau I (2015) PD-1 and PD-L1 blockade in gastrointestinal malignancies. Cancer Treat Rev 41(10):893–903. doi: 10.1016/j.ctrv.2015.09.004 CrossRefPubMedGoogle Scholar
  4. 4.
    Patel SP, Kurzrock R (2015) PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 14(4):847–856. doi: 10.1158/1535-7163.MCT-14-0983 CrossRefPubMedGoogle Scholar
  5. 5.
    Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ (2007) The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 8(3):239–245. doi: 10.1038/ni1443 CrossRefPubMedGoogle Scholar
  6. 6.
    Sznol M, Chen L (2013) Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res 19(5):1021–1034. doi: 10.1158/1078-0432.CCR-12-2063 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Loos M, Langer R, Schuster T, Gertler R, Walch A, Rauser S, Friess H, Feith M (2011) Clinical significance of the costimulatory molecule B7-H1 in Barrett carcinoma. Ann Thorac Surg 91(4):1025–1031. doi: 10.1016/j.athoracsur.2010.12.041 CrossRefPubMedGoogle Scholar
  8. 8.
    Derks S, Nason KS, Liao X, Stachler MD, Liu KX, Liu JB, Sicinska E, Goldberg MS, Freeman GJ, Rodig SJ, Davison JM, Bass AJ (2015) Epithelial PD-l2 expression marks Barrett’s esophagus and esophageal adenocarcinoma. Cancer Immunol Res 3(10):1123–1129. doi: 10.1158/2326-6066.CIR-15-0046 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ilie M, Hofman V, Dietel M, Soria JC, Hofman P (2016) Assessment of the PD-L1 status by immunohistochemistry: challenges and perspectives for therapeutic strategies in lung cancer patients. Virchows Arch 468(5):511–525. doi: 10.1007/s00428-016-1910-4 CrossRefPubMedGoogle Scholar
  10. 10.
    Kerr KM, Hirsch FR (2016) Programmed death ligand-1 immunohistochemistry: friend or foe? Arch Pathol Lab Med 140(4):326–331. doi: 10.5858/arpa.2015-0522-SA CrossRefPubMedGoogle Scholar
  11. 11.
    Ma W, Gilligan BM, Yuan J, Li T (2016) Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hematol Oncol 9(1):47. doi: 10.1186/s13045-016-0277-y CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Zlobec I, Koelzer VH, Dawson H, Perren A, Lugli A (2013) Next-generation tissue microarray (ngTMA) increases the quality of biomarker studies: an example using CD3, CD8, and CD45RO in the tumor microenvironment of six different solid tumor types. J Transl Med 11:104. doi: 10.1186/1479-5876-11-104 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Zlobec I, Minoo P, Terracciano L, Baker K, Lugli A (2011) Characterization of the immunological microenvironment of tumour buds and its impact on prognosis in mismatch repair-proficient and -deficient colorectal cancers. Histopathology 59(3):482–495. doi: 10.1111/j.1365-2559.2011.03975.x CrossRefPubMedGoogle Scholar
  14. 14.
    Stein AV, Dislich B, Blank A, Guldener L, Kröll D, Seiler CA, Langer R (2017) High intratumoural but not peritumoural inflammatory host response is associated with better prognosis in primary resected oesophageal adenocarcinomas. Pathology 49(1):30–37. doi: 10.1016/j.pathol.2016.10.005 CrossRefPubMedGoogle Scholar
  15. 15.
    Scheel AH, Dietel M, Heukamp LC, Jöhrens K, Kirchner T, Reu S, Rüschoff J, Schildhaus HU, Schirmacher P, Tiemann M, Warth A, Weichert W, Fischer RN, Wolf J, Buettner R (2016) Harmonized PD-L1 immunohistochemistry for pulmonary squamous-cell and adenocarcinomas. Mod Pathol 29(10):1165–1172. doi: 10.1038/modpathol.2016.117 CrossRefPubMedGoogle Scholar
  16. 16.
    Gaule P, Smithy JW, Toki M, Rehman J, Patell-Socha F, Cougot D, Collin P, Morrill P, Neumeister V, Rimm DL (2016) A quantitative comparison of antibodies to programmed cell death 1 ligand 1. JAMA Oncol. doi: 10.1001/jamaoncol.2016.3015 PubMedGoogle Scholar
  17. 17.
    Powles T, Nickles D, Van Allen E, Chappey C, Zou W, Kowanetz M, Mariathasan S (2015) Immune biomarkers associated with clinical benefit from atezolizumab (MPDL3280a; anti-PD-L1) in advanced urothelial bladder cancer (UBC). J Immunother Cancer 3(Suppl 2):P83. doi: 10.1186/2051-1426-3-S2-P83 CrossRefPubMedCentralGoogle Scholar
  18. 18.
    Apolo AB (2016) PDL1: the illusion of an ideal biomarker. Eur Urol Focus 1(3):269–271. doi: 10.1016/j.euf.2015.04.005 CrossRefGoogle Scholar
  19. 19.
    Goldberg SB (2015) PD-1 and PD-L1 inhibitors: activity as single agents and potential biomarkers in non-small cell lung cancer. Am J Hematol Oncol 11(9):10–13Google Scholar
  20. 20.
    Droeser RA, Hirt C, Viehl CT, Frey DM, Nebiker C, Huber X, Zlobec I, Eppenberger-Castori S, Tzankov A, Rosso R, Zuber M, Muraro MG, Amicarella F, Cremonesi E, Heberer M, Iezzi G, Lugli A, Terracciano L, Sconocchia G, Oertli D, Spagnoli GC, Tornillo L (2013) Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer 49(9):2233–2242. doi: 10.1016/j.ejca.2013.02.015 CrossRefPubMedGoogle Scholar
  21. 21.
    Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571. doi: 10.1038/nature13954 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Teng MW, Ngiow SF, Ribas A, Smyth MJ (2015) Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 75(11):2139–2145. doi: 10.1158/0008-5472.CAN-15-0255 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8(8):793–800. doi: 10.1038/nm730 PubMedGoogle Scholar
  24. 24.
    Qing Y LQ, Ren T, Xia W, Peng Y, Liu GL, Luo H, Yang YX, Dai XY, Zhou SF, Wang D (2015) Upregulation of PD-L1 and APE1 is associated with tumorigenesis and poor prognosis of gastric cancer. Drug Des Dev Ther 9:901–909. doi: 10.2147/DDDT.S75152 CrossRefGoogle Scholar
  25. 25.
    Boger C, Behrens HM, Mathiak M, Kruger S, Kalthoff H, Rocken C (2016) PD-L1 is an independent prognostic predictor in gastric cancer of Western patients. Oncotarget 7(17):24269–24283. doi: 10.18632/oncotarget.8169 PubMedPubMedCentralGoogle Scholar
  26. 26.
    Masugi Y, Nishihara R, Yang J, Mima K, da Silva A, Shi Y, Inamura K, Cao Y, Song M, Nowak JA, Liao X, Nosho K, Chan AT, Giannakis M, Bass AJ, Hodi FS, Freeman GJ, Rodig S, Fuchs CS, Qian ZR, Ogino S (2016) Tumour CD274 (PD-L1) expression and T cells in colorectal cancer. Gut. doi: 10.1136/gutjnl-2016-311421 Google Scholar
  27. 27.
    Dauffenbach L, Sia G, Cash P, Girees S, Lim R, Zheng J, Olsen E, Kerfoot C (2015) Optimization of an assay for the detection of PD-L1 by immunohistochemistry in formalin-fixed, paraffin-embedded human tissue and cell lines. Cancer Res 75(15 Suppl):Abstract nr 3396. doi: 10.1158/1538-7445.AM2015-3396 (Abstract from AACR 106th Annual Meeting, Philadelphia, PA, USA, April 18–22 2015)CrossRefGoogle Scholar
  28. 28.
    Hodi FS, Sznol M, Kluger HM, McDermott DF, Carvajal RD, Lawrence DP (2014) Long-term survival of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) in a phase I trial. J Clin Oncol 32:5s (Abstract from ASCO 50th Annual Meeting, Chicago, IL, USA, June 3 2014)Google Scholar
  29. 29.
    Raufi AG, Klempner SJ (2015) Immunotherapy for advanced gastric and esophageal cancer: preclinical rationale and ongoing clinical investigations. J Gastrointest Oncol 6(5):561–569. doi: 10.3978/j.issn.2078-6891.2015.037 PubMedPubMedCentralGoogle Scholar
  30. 30.
    Romano E, Romero P (2015) The therapeutic promise of disrupting the PD-1/PD-L1 immune checkpoint in cancer: unleashing the CD8 T cell mediated anti-tumor activity results in significant, unprecedented clinical efficacy in various solid tumors. J Immunother Cancer 3:15. doi: 10.1186/s40425-015-0059-z CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Callea M, Albiges L, Gupta M, Cheng SC, Genega EM, Fay AP, Song J, Carvo I, Bhatt RS, Atkins MB, Hodi FS, Choueiri TK, McDermott DF, Freeman GJ, Signoretti S (2015) Differential expression of PD-L1 between primary and metastatic sites in clear-cell renal cell carcinoma. Cancer Immunol Res 3(10):1158–1164. doi: 10.1158/2326-6066.CIR-15-0043 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Riaz N, Morris L, Havel JJ, Makarov V, Desrichard A, Chan TA (2016) The role of neoantigens in response to immune checkpoint blockade. Int Immunol 28(8):411–419. doi: 10.1093/intimm/dxw019 CrossRefPubMedGoogle Scholar
  33. 33.
    Inaguma S, Lasota J, Wang Z, Felisiak-Golabek A, Ikeda H, Miettinen M (2017) Clinicopathologic profile, immunophenotype, and genotype of CD274 (PD-L1)-positive colorectal carcinomas. Mod Pathol 30(2):278–285. doi: 10.1038/modpathol.2016.185 CrossRefPubMedGoogle Scholar
  34. 34.
    Kawazoe A, Kuwata T, Kuboki Y, Shitara K, Nagatsuma AK, Aizawa M, Yoshino T, Doi T, Ohtsu A, Ochiai A (2016) Clinicopathological features of programmed death ligand 1 expression with tumor-infiltrating lymphocyte, mismatch repair, and Epstein-Barr virus status in a large cohort of gastric cancer patients. Gastric Cancer. doi: 10.1007/s10120-016-0631-3 PubMedGoogle Scholar
  35. 35.
    Genitsch V, Novotny A, Seiler CA, Kroll D, Walch A, Langer R (2015) Epstein–Barr virus in gastro-esophageal adenocarcinomas - single center experiences in the context of current literature. Front Oncol 5:73. doi: 10.3389/fonc.2015.00073 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L (2012) Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 4(127):127ra137. doi: 10.1126/scitranslmed.3003689 CrossRefGoogle Scholar
  37. 37.
    Muenst S, Soysal SD, Tzankov A, Hoeller S (2015) The PD-1/PD-L1 pathway: biological background and clinical relevance of an emerging treatment target in immunotherapy. Expert Opin Ther Targets 19(2):201–211. doi: 10.1517/14728222.2014.980235 CrossRefPubMedGoogle Scholar
  38. 38.
    Sheng J, Fang W, Yu J, Chen N, Zhan J, Ma Y, Yang Y, Yanhuang, Zhao H, Zhang L (2016) Expression of programmed death ligand-1 on tumor cells varies pre and post chemotherapy in non-small cell lung cancer. Sci Rep 6:20090. doi: 10.1038/srep20090 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Zhang P, Su DM, Liang M, Fu J (2008) Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis. Mol Immunol 45(5):1470–1476. doi: 10.1016/j.molimm.2007.08.013 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Bastian Dislich
    • 1
  • Alexandra Stein
    • 1
  • Christian A. Seiler
    • 2
  • Dino Kröll
    • 2
  • Sabina Berezowska
    • 1
  • Inti Zlobec
    • 1
  • José Galvan
    • 1
  • Julia Slotta-Huspenina
    • 3
  • Axel Walch
    • 4
  • Rupert Langer
    • 1
    Email author
  1. 1.Institute of PathologyUniversity of BernBernSwitzerland
  2. 2.Department of Visceral Surgery and MedicineInselspital University Hospital Bern, University BernBernSwitzerland
  3. 3.Institute of PathologyTechnical University of MunichMunichGermany
  4. 4.Research Unit Analytical Pathology, Helmholtz Center MunichGerman Research Center for Environmental HealthOberschleißheimGermany

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