Journal of Cancer Research and Clinical Oncology

, Volume 144, Issue 7, pp 1219–1226 | Cite as

Chemotherapy treatment is associated with altered PD-L1 expression in lung cancer patients

  • Lívia Rojkó
  • Lilla Reiniger
  • Vanda Téglási
  • Katalin Fábián
  • Orsolya Pipek
  • Attila Vágvölgyi
  • László Agócs
  • János Fillinger
  • Zita Kajdácsi
  • József Tímár
  • Balázs Döme
  • Zoltán Szállási
  • Judit Moldvay
Original Article – Cancer Research

Abstract

Objectives

While the predictive value of programmed cell death ligand-1 (PD-L1) protein expression for immune checkpoint inhibitor therapy of lung cancer has been extensively studied, the impact of standard platinum-based chemotherapy on PD-L1 or programmed cell death-1 (PD-1) expression is unknown. The aim of this study was to determine the changes in PD-L1 expression of tumor cells (TC) and immune cells (IC), in PD-1 expression of IC, and in the amount of stromal mononuclear cell infiltration after platinum-based chemotherapy in patients with lung cancer.

Materials and methods

We determined the amount of stromal mononuclear cells and PD-L1/PD-1 expressions by immunohistochemistry in bronchoscopic biopsy samples including 20 adenocarcinomas (ADC), 15 squamous cell carcinomas (SCC), 2 other types of non-small cell lung cancer, and 4 small cell lung cancers together with their corresponding surgical resection tissues after platinum-based chemotherapy.

Results

PD-L1 expression of TC decreased in ten patients (24.4%) and increased in three patients (7.32%) after neoadjuvant chemotherapy (p = 0.051). The decrease in PD-L1 expression, however, was significant only in patients who received cisplatin–gemcitabine combination (p = 0.020), while in the carboplatin–paclitaxel group, no similar tendency could be observed (p = 0.432). There was no difference between ADC and SCC groups. Neither PD-1 expression nor the amount of stromal IC infiltration showed significant changes after chemotherapy.

Conclusions

This is the first study, in which both PD-L1 and PD-1 expression were analyzed together with the amount of stromal IC infiltration in different histological subtypes of lung cancer before and after platinum-based chemotherapy. Our results confirm that chemotherapy decreases PD-L1 expression of TC in a subset of patients, therefore, rebiopsy and re-evaluation of PD-L1 expression may be necessary for the indication of immune checkpoint inhibitor therapy.

Keywords

PD-L1 PD-1 Immunohistochemistry Lung cancer Chemotherapy 

Abbreviations

ADC

Adenocarcinoma

ADSQ

Adenosquamous carcinoma

IC

Immune cells

IHC

Immunohistochemistry

MEC

Mucoepidermoid carcinoma

NSCLC

Non-small cell lung cancer

PD-L1

Programmed cell death ligand-1

PD-1

Programmed cell death-1

SCC

Squamous cell carcinoma

SCLC

Small cell lung cancer

TC

Tumor cells

Notes

Acknowledgements

We thank Zsuzsanna Kaminszky, Anna Tamási and Mónika Szilágyiné Paulusz for their excellent technical assistance, and Ildikó Krencz for constructing the tissue microarray (TMA) blocks.

Funding

This work was supported by the Research and Technology Innovation Fund (KTIA_NAP_13-2014-0021 to L.R., Z.S., J.M.); Hungarian Science Foundation (OTKA-PD115792 to L.R., OTKA-K116151 to L.R., J.T., B.D., OTKA-K112371 to J.T.); Breast Cancer Research Foundation and the Novo Nordisk Foundation Interdisciplinary Synergy Programme Grant (NNF15OC0016584 to Z.S.). For the remaining authors none were declared.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

Permissions to use the archived tissue have been obtained from the Regional Ethical Committee (Nos: 510/2013, 86/2015, 241/2016).

References

  1. Chacon JA, Schutsky K, Powell DJ (2016) The impact of chemotherapy, radiation and epigenetic modifiers in cancer cell expression of immune inhibitory and stimulatory molecules and anti-tumor efficacy. Vaccines 4(4): 43.  https://doi.org/10.3390/vaccines4040043 CrossRefPubMedCentralGoogle Scholar
  2. Cheng TY, Cramb SM, Baade PD, Youlden DR, Nwogu C, Reid ME,, and Characteristics T (2016) The international epidemiology of lung cancer: latest trends, disparities. J Thorac Oncol 11(10):1653–1671.  https://doi.org/10.1016/j.jtho.2016.05.021 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Doi T, Ishikawa T, Okayama T, Oka K, Mizushima K, Yasuda T, Sakamoto N, Katada K, Kamada K, Uchiyama K, Handa O, Takagi T, Naito Y, Itoh Y (2017) The JAK/STAT pathway is involved in the upregulation of PD-L1 expression in pancreatic cancer cell lines. Oncol Rep 37(3):1545–1554.  https://doi.org/10.3892/or.2017.5399 CrossRefPubMedGoogle Scholar
  4. Festino L, Botti G, Lorigan P, Masucci GV, Hipp JD, Horak CE, Melero I, Ascierto PA, Cancer treatment with anti-PD-1/PD-L1 agents: is PD-L1 expression a biomarker for patient selection? Drugs 76(9) (2016) 925–45.  https://doi.org/10.1007/s40265-016-0588-x
  5. Ghebeh H, Lehe C, Barhoush E, Al-Romaih K, Tulbah A, Al-Alwan M, Hendrayani SF, Manogaran P, Alaiya A, Al-Tweigeri T, Aboussekhra A, Dermime S (2010) Doxorubicin downregulates cell surface B7-H1 expression and upregulates its nuclear expression in breast cancer cells: role of B7-H1 as an anti-apoptotic molecule. Breast Cancer Res BCR 12(4):R48.  https://doi.org/10.1186/bcr2605 CrossRefPubMedGoogle Scholar
  6. Kerr KM, Nicolson MC, Non-small cell lung cancer, PD-L1, and the pathologist. Arch Pathol Lab Med 140(3) (2016) 249–54.  https://doi.org/10.5858/arpa.2015-0303-SA
  7. Li Q, Yuan D, Ma C, Liu Y, Ma L, Lv T, Song Y, A new hope: the immunotherapy in small cell lung cancer. Neoplasma 63(3) (2016) 342–350.  https://doi.org/10.4149/302_151001n511
  8. Meert AP, Martin B, Verdebout JM, Paesmans M, Berghmans T, Ninane V, Sculier JP (2004) Correlation of different markers (p53, EGF-R, c-erbB-2, Ki-67) expression in the diagnostic biopsies and the corresponding resected tumors in non-small cell lung cancer. Lung Cancer (Amsterdam Netherlands) 44(3):295–301.  https://doi.org/10.1016/j.lungcan.2003.12.009 CrossRefGoogle Scholar
  9. Munari E, Zamboni G, Marconi M, Sommaggio M, Brunelli M, Martignoni G, Netto GJ, Moretta F, Mingari MC, Salgarello M, Terzi A, Picece V, Pomari C, Lunardi G, Cavazza A, Rossi G, Moretta L, Bogina G (2017) PD-L1 expression heterogeneity in non-small cell lung cancer: evaluation of small biopsies reliability. Oncotarget 8(52):90123–90131.  https://doi.org/10.18632/oncotarget.21485 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Passiglia F, Bronte G, Bazan V, Natoli C, Rizzo S, Galvano A, Listi A, Cicero G, Rolfo C, Santini D, Russo A (2016) PD-L1 expression as predictive biomarker in patients with NSCLC: a pooled analysis. Oncotarget 7(15):19738-47.  https://doi.org/10.18632/oncotarget.7582 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Peng J, Hamanishi J, Matsumura N, Abiko K, Murat K, Baba T, Yamaguchi K, Horikawa N, Hosoe Y, Murphy SK, Konishi I, Mandai M (2015) Chemotherapy induces programmed cell death-ligand 1 overexpression via the nuclear factor-kappaB to foster an immunosuppressive tumor microenvironment in ovarian cancer. Cancer Res 75(23):5034-5045.  https://doi.org/10.1158/0008-5472.can-14-3098 CrossRefPubMedGoogle Scholar
  12. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. New Engl J Med 375(19):1823–1833.  https://doi.org/10.1056/NEJMoa1606774 CrossRefPubMedGoogle Scholar
  13. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, Wienert S, Van den Eynden G, Baehner FL, Penault-Llorca F, Perez EA, Thompson EA, Symmans WF, Richardson AL, Brock J, Criscitiello C, Bailey H, Ignatiadis M, Floris G, Sparano J, Kos Z, Nielsen T, Rimm DL, Allison KH, Reis-Filho JS, Loibl S, Sotiriou C, Viale G, Badve S, Adams S, Willard-Gallo K, Loi S, The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26(2) (2015) 259–271.  https://doi.org/10.1093/annonc/mdu450
  14. Sheng J, Fang W, Yu J, Chen N, Zhan J, Ma Y, Yang Y, Huang Y, 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.  https://doi.org/10.1038/srep20090 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Spira AI, Park K, Mazières J, Vansteenkiste JF, Rittmeyer A, Ballinger M, Waterkamp D, Kowanetz M, Mokatrin A, Fehrenbacher L (2015) Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR). J Clin Oncol 33(15_suppl): 8010–8010.  https://doi.org/10.1200/jco.2015.33.15_suppl.8010 Google Scholar
  16. Teglasi V, Reiniger L, Fabian K, Pipek O, Csala I, Bago AG, Varallyai P, Vizkeleti L, Rojko L, Timar J, Dome B, Szallasi Z, Swanton C, Moldvay J (2017) Evaluating the significance of density, localization, and PD-1/PD-L1 immunopositivity of mononuclear cells in the clinical course of lung adenocarcinoma patients with brain metastasis. Neuro Oncol.  https://doi.org/10.1093/neuonc/now309 PubMedGoogle Scholar
  17. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, Garg K, Austin JH, Asamura H, Rusch VW, Hirsch FR, Scagliotti G, Mitsudomi T, Huber RM, Ishikawa Y, Jett J, Sanchez-Cespedes M, Sculier JP, Takahashi T, Tsuboi M, Vansteenkiste J, Wistuba I, Yang PC, Aberle D, Brambilla C, Flieder D, Franklin W, Gazdar A, Gould M, Hasleton P, Henderson D, Johnson B, Johnson D, Kerr K, Kuriyama K, Lee JS, Miller VA, Petersen I, Roggli V, Rosell R, Saijo N, Thunnissen E, Tsao M, Yankelewitz D (2011) International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 6(2) 244–285.  https://doi.org/10.1097/JTO.0b013e318206a221 CrossRefGoogle Scholar
  18. Yang CY, Lin MW, Chang YL, Wu CT, Yang PC (1990) Programmed cell death-ligand 1 expression is associated with a favourable immune microenvironment and better overall survival in stage I pulmonary squamous cell carcinoma. Eur J Cancer (Oxford England) 57:(2016) 91–103.  https://doi.org/10.1016/j.ejca.2015.12.033 Google Scholar
  19. 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):1470-6.  https://doi.org/10.1016/j.molimm.2007.08.013 CrossRefPubMedGoogle Scholar
  20. Zhang P, Ma Y, Lv C, Huang M, Li M, Dong B, Liu X, An G, Zhang W, Zhang J, Zhang L, Zhang S, Yang Y (2016) Upregulation of programmed cell death ligand 1 promotes resistance response in non-small-cell lung cancer patients treated with neo-adjuvant chemotherapy. Cancer Sci 107(11):1563–1571.  https://doi.org/10.1111/cas.13072 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Lívia Rojkó
    • 1
  • Lilla Reiniger
    • 2
    • 3
  • Vanda Téglási
    • 2
  • Katalin Fábián
    • 4
    • 5
  • Orsolya Pipek
    • 6
  • Attila Vágvölgyi
    • 7
  • László Agócs
    • 8
  • János Fillinger
    • 9
    • 10
  • Zita Kajdácsi
    • 9
  • József Tímár
    • 11
  • Balázs Döme
    • 12
    • 13
  • Zoltán Szállási
    • 3
    • 14
    • 15
  • Judit Moldvay
    • 1
    • 3
  1. 1.VI. Department of PulmonologyNational Korányi Institute of PulmonologyBudapestHungary
  2. 2.1st Department of Pathology and Experimental Cancer ResearchSemmelweis UniversityBudapestHungary
  3. 3.MTA-SE NAP, Brain Metastasis Research Group, 2nd Department of Pathology, Hungarian Academy of SciencesSemmelweis UniversityBudapestHungary
  4. 4.Department of PulmonologySemmelweis UniversityBudapestHungary
  5. 5.Department of PathologySzent Imre Teaching HospitalBudapestHungary
  6. 6.Department of Physics of Complex SystemsEötvös Loránd UniversityBudapestHungary
  7. 7.Department of Thoracic SurgeryNational Korányi Institute of PulmonologyBudapestHungary
  8. 8.Department of Thoracic SurgeryNational Institute of Oncology-Semmelweis UniversityBudapestHungary
  9. 9.Department of PathologyNational Korányi Institute of PulmonologyBudapestHungary
  10. 10.Department of PathologyNational Institute of OncologyBudapestHungary
  11. 11.2nd Department of PathologySemmelweis UniversityBudapestHungary
  12. 12.Department of Tumor BiologyNational Korányi Institute of Pulmonology-Semmelweis UniversityBudapestHungary
  13. 13.Comprehensive Cancer Center, Division of Thoracic SurgeryMedical University of ViennaViennaAustria
  14. 14.Children’s Hospital Informatics Program at the Harvard–Massachusetts Institute of Technology, Division of Health Sciences and TechnologyHarvard Medical SchoolBostonUSA
  15. 15.Department of Bio and Health InformaticsTechnical University of DenmarkKongens LyngbyDenmark

Personalised recommendations