Skip to main content

Advertisement

SpringerLink
Log in

Clinicopathological features of programmed cell death-1 and programmed cell death-ligand-1 expression in the tumor cells and tumor microenvironment of angioimmunoblastic T cell lymphoma and peripheral T cell lymphoma not otherwise specified

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

The expression patterns of programmed cell death-1 (PD-1) and programmed cell death-ligand-1 (PD-L1) and their clinicopathological implications were investigated in peripheral T cell lymphoma (PTCL) including angioimmunoblastic T cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS). PTCL-NOS was further classified into nodal PTCL with follicular helper T cell (Tfh) phenotype (“PTCL-Tfh_new”) and “PTCL-NOS_new”. PD-1 and PD-L1 expression on tumor cells and reactive immune cells was evaluated using immunohistochemistry. PD-1 and PD-L1 expression on tumor cells (PD-1T and PD-L1T, respectively) was interpreted as positive when more than 5% of tumor cells expressed PD-1 or PD-L1. For PD-1 and PD-L1 on tumor cells and/or reactive immune cells (PD-1T + IC and PD-L1T + IC, respectively), a cutoff of 10% of cells was used. PD-1T, PD-L1T, and PD-L1T + IC expressions tended to be higher in AITLs than in PTCLs-NOS. PD-1T, PD-1T + IC, PD-L1T, and PD-L1T + IC expressions tended to be higher in PTCLs with Tfh phenotype including AITLs and “PTCL-Tfh_new” than in PTCLs without Tfh phenotype. The serum LDH level was significantly elevated in patients with PTCL positive for PD-L1T (P = 0.006) and PD-L1T + IC (P < 0.001). Patients with PTCL who were positive for combined expression of PD-1T/PD-L1T + IC presented at older ages (P = 0.010), nodal diseases (P = 0.001), higher IPI (P = 0.060), and elevated LDH (P = 0.030). Combined PD-1T/PD-L1T + IC positivity was related to shorter overall survival in patients with AITL (P = 0.051). Combined PD-1T/PD-L1T + IC positivity was a significant poor prognostic factor in patients with stage IV AITL, independent of B symptoms and performance status (HR = 6.282 [CI, 1.655–23.844], P = 0.007). In summary, the PD-1/PD-L1 pathway could be a potential prognostic and therapeutic biomarker for PTCL.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Jaffe ES, Nicolae A, Pittaluga S (2013) Peripheral T-cell and NK-cell lymphomas in the WHO classification: pearls and pitfalls. Modern pathology : an official journal of the United States and Canadian Academy Of Pathology, Inc 26(Suppl 1):S71–S87. https://doi.org/10.1038/modpathol.2012.181

    Article  CAS  Google Scholar 

  2. Iqbal J, Wilcox R, Naushad H, Rohr J, Heavican TB, Wang C, Bouska A, Fu K, Chan WC, Vose JM (2016) Genomic signatures in T-cell lymphoma: how can these improve precision in diagnosis and inform prognosis? Blood Rev 30(2):89–100. https://doi.org/10.1016/j.blre.2015.08.003

    Article  CAS  PubMed  Google Scholar 

  3. de Leval L, Rickman DS, Thielen C, Reynies A, Huang YL, Delsol G, Lamant L, Leroy K, Briere J, Molina T, Berger F, Gisselbrecht C, Xerri L, Gaulard P (2007) The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood 109(11):4952–4963. https://doi.org/10.1182/blood-2006-10-055145

    Article  CAS  PubMed  Google Scholar 

  4. Dobay MP, Lemonnier F, Missiaglia E, Bastard C, Vallois D, Jais JP, Scourzic L, Dupuy A, Fataccioli V, Pujals A, Parrens M, Le Bras F, Rousset T, Picquenot JM, Martin N, Haioun C, Delarue R, Bernard OA, Delorenzi M, de Leval L, Gaulard P (2017) Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin. Haematologica 102(4):e148–e151. https://doi.org/10.3324/haematol.2016.158428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES (2016) The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 127(20):2375–2390. https://doi.org/10.1182/blood-2016-01-643569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lunning MA, Vose JM (2017) Angioimmunoblastic T-cell lymphoma: the many-faced lymphoma. Blood 129(9):1095–1102. https://doi.org/10.1182/blood-2016-09-692541

    Article  CAS  PubMed  Google Scholar 

  7. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. https://doi.org/10.1038/nrc3239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27(4):450–461. https://doi.org/10.1016/j.ccell.2015.03.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ribas A, Wolchok JD (2018) Cancer immunotherapy using checkpoint blockade. Science 359(6382):1350–1355. https://doi.org/10.1126/science.aar4060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen BJ, Chapuy B, Ouyang J, Sun HH, Roemer MG, Xu ML, Yu H, Fletcher CD, Freeman GJ, Shipp MA, Rodig SJ (2013) PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin J Am Assoc Cancer Res 19(13):3462–3473. https://doi.org/10.1158/1078-0432.CCR-13-0855

    Article  CAS  Google Scholar 

  11. Goodman A, Patel SP, Kurzrock R (2017) PD-1-PD-L1 immune-checkpoint blockade in B-cell lymphomas. Nat Rev Clin Oncol 14(4):203–220. https://doi.org/10.1038/nrclinonc.2016.168

    Article  CAS  PubMed  Google Scholar 

  12. Marzec M, Zhang Q, Goradia A, Raghunath PN, Liu X, Paessler M, Wang HY, Wysocka M, Cheng M, Ruggeri BA, Wasik MA (2008) Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci U S A 105(52):20852–20857. https://doi.org/10.1073/pnas.0810958105

    Article  PubMed  PubMed Central  Google Scholar 

  13. Panjwani PK, Charu V, DeLisser M, Molina-Kirsch H, Natkunam Y, Zhao S (2018) Programmed death-1 ligands PD-L1 and PD-L2 show distinctive and restricted patterns of expression in lymphoma subtypes. Hum Pathol 71:91–99. https://doi.org/10.1016/j.humpath.2017.10.029

    Article  CAS  PubMed  Google Scholar 

  14. Gibbons Johnson RM, Dong H (2017) Functional expression of programmed death-ligand 1 (B7-H1) by immune cells and tumor cells. Front Immunol 8:961. https://doi.org/10.3389/fimmu.2017.00961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tse E, Kwong YL (2015) T-cell lymphoma: microenvironment-related biomarkers. Semin Cancer Biol 34:46–51. https://doi.org/10.1016/j.semcancer.2015.06.001

    Article  CAS  PubMed  Google Scholar 

  16. Krishnan C, Warnke RA, Arber DA, Natkunam Y (2010) PD-1 expression in T-cell lymphomas and reactive lymphoid entities: potential overlap in staining patterns between lymphoma and viral lymphadenitis. Am J Surg Pathol 34(2):178–189. https://doi.org/10.1097/PAS.0b013e3181cc7e79

    Article  PubMed  Google Scholar 

  17. Kim S, Nam SJ, Park C, Kwon D, Yim J, Song SG, Ock CY, Kim YA, Park SH, Kim TM, Jeon YK (2019) High tumoral PD-L1 expression and low PD-1(+) or CD8(+) tumor-infiltrating lymphocytes are predictive of a poor prognosis in primary diffuse large B-cell lymphoma of the central nervous system. Oncoimmunology 8(9):e1626653. https://doi.org/10.1080/2162402X.2019.1626653

    Article  PubMed  PubMed Central  Google Scholar 

  18. Schatz JH, Horwitz SM, Teruya-Feldstein J, Lunning MA, Viale A, Huberman K, Socci ND, Lailler N, Heguy A, Dolgalev I, Migliacci JC, Pirun M, Palomba ML, Weinstock DM, Wendel HG (2015) Targeted mutational profiling of peripheral T-cell lymphoma not otherwise specified highlights new mechanisms in a heterogeneous pathogenesis. Leukemia 29(1):237–241. https://doi.org/10.1038/leu.2014.261

    Article  CAS  PubMed  Google Scholar 

  19. Wartewig T, Kurgyis Z, Keppler S, Pechloff K, Hameister E, Ollinger R, Maresch R, Buch T, Steiger K, Winter C, Rad R, Ruland J (2017) PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature 552(7683):121–125. https://doi.org/10.1038/nature24649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ahearne MJ, Allchin RL, Fox CP, Wagner SD (2014) Follicular helper T-cells: expanding roles in T-cell lymphoma and targets for treatment. Br J Haematol 166(3):326–335. https://doi.org/10.1111/bjh.12941

    Article  CAS  PubMed  Google Scholar 

  21. Xerri L, Chetaille B, Serriari N, Attias C, Guillaume Y, Arnoulet C, Olive D (2008) Programmed death 1 is a marker of angioimmunoblastic T-cell lymphoma and B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia. Hum Pathol 39(7):1050–1058. https://doi.org/10.1016/j.humpath.2007.11.012

    Article  CAS  PubMed  Google Scholar 

  22. Jelinek T, Mihalyova J, Kascak M, Duras J, Hajek R (2017) PD-1/PD-L1 inhibitors in haematological malignancies: update 2017. Immunology 152(3):357–371. https://doi.org/10.1111/imm.12788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (2008) WHO classification of tumours of haematopoietic and lymphoid tissues. International Agency for Research on Cancer, Lyon

    Google Scholar 

  24. Kwon D, Kim S, Kim PJ, Go H, Nam SJ, Paik JH, Kim YA, Kim TM, Heo DS, Kim CW, Jeon YK (2016) Clinicopathological analysis of programmed cell death 1 and programmed cell death ligand 1 expression in the tumour microenvironments of diffuse large B cell lymphomas. Histopathology 68(7):1079–1089. https://doi.org/10.1111/his.12882

    Article  PubMed  Google Scholar 

  25. Zaja F, Tabanelli V, Agostinelli C, Calleri A, Chiappella A, Varettoni M, Luigi Zinzani P, Volpetti S, Sabattini E, Fanin R, Pileri SA (2017) CD38, BCL-2, PD-1, and PD-1L expression in nodal peripheral T-cell lymphoma: possible biomarkers for novel targeted therapies? Am J Hematol 92(1):E1–E2. https://doi.org/10.1002/ajh.24571

    Article  CAS  PubMed  Google Scholar 

  26. Wilcox RA, Feldman AL, Wada DA, Yang ZZ, Comfere NI, Dong H, Kwon ED, Novak AJ, Markovic SN, Pittelkow MR, Witzig TE, Ansell SM (2009) B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders. Blood 114(10):2149–2158. https://doi.org/10.1182/blood-2009-04-216671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sakakibara A, Kohno K, Eladl AE, Klaisuwan T, Ishikawa E, Suzuki Y, Shimada S, Nakaguro M, Shimoyama Y, Takahara T, Kato S, Asano N, Nakamura S, Satou A (2018) Immunohistochemical assessment of the diagnostic utility of PD-L1: a preliminary analysis of anti-PD-L1 antibody (SP142) for lymphoproliferative diseases with tumour and non-malignant Hodgkin-Reed-Sternberg (HRS)-like cells. Histopathology 72(7):1156–1163. https://doi.org/10.1111/his.13475

    Article  PubMed  Google Scholar 

  28. Green MR, Rodig S, Juszczynski P, Ouyang J, Sinha P, O'Donnell E, Neuberg D, Shipp MA (2012) Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin J Am Assoc Cancer Res 18(6):1611–1618. https://doi.org/10.1158/1078-0432.CCR-11-1942

    Article  CAS  Google Scholar 

  29. Dupuis J, Emile JF, Mounier N, Gisselbrecht C, Martin-Garcia N, Petrella T, Bouabdallah R, Berger F, Delmer A, Coiffier B, Reyes F, Gaulard P, Groupe d'Etude des Lymphomes de lA (2006) Prognostic significance of Epstein-Barr virus in nodal peripheral T-cell lymphoma, unspecified: a Groupe d'Etude des Lymphomes de l'Adulte (GELA) study. Blood 108(13):4163–4169. https://doi.org/10.1182/blood-2006-04-017632

    Article  CAS  PubMed  Google Scholar 

  30. Ng SB, Chung TH, Kato S, Nakamura S, Takahashi E, Ko YH, Khoury JD, Yin CC, Soong R, Jeyasekharan AD, Hoppe MM, Selvarajan V, Tan SY, Lim ST, Ong CK, Nairismagi ML, Maheshwari P, Choo SN, Fan S, Lee CK, Chuang SS, Chng WJ (2018) Epstein-Barr virus-associated primary nodal T/NK-cell lymphoma shows a distinct molecular signature and copy number changes. Haematologica 103(2):278–287. https://doi.org/10.3324/haematol.2017.180430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gravelle P, Burroni B, Pericart S, Rossi C, Bezombes C, Tosolini M, Damotte D, Brousset P, Fournie JJ, Laurent C (2017) Mechanisms of PD-1/PD-L1 expression and prognostic relevance in non-Hodgkin lymphoma: a summary of immunohistochemical studies. Oncotarget 8(27):44960–44975. https://doi.org/10.18632/oncotarget.16680

    Article  PubMed  PubMed Central  Google Scholar 

  32. Carreras J, Lopez-Guillermo A, Roncador G, Villamor N, Colomo L, Martinez A, Hamoudi R, Howat WJ, Montserrat E, Campo E (2009) High numbers of tumor-infiltrating programmed cell death 1-positive regulatory lymphocytes are associated with improved overall survival in follicular lymphoma. J Clin Oncol 27(9):1470–1476. https://doi.org/10.1200/jco.2008.18.0513

    Article  PubMed  Google Scholar 

  33. Kiyasu J, Miyoshi H, Hirata A, Arakawa F, Ichikawa A, Niino D, Sugita Y, Yufu Y, Choi I, Abe Y, Uike N, Nagafuji K, Okamura T, Akashi K, Takayanagi R, Shiratsuchi M, Ohshima K (2015) Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood 126(19):2193–2201. https://doi.org/10.1182/blood-2015-02-629600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Miyoshi H, Kiyasu J, Kato T, Yoshida N, Shimono J, Yokoyama S, Taniguchi H, Sasaki Y, Kurita D, Kawamoto K, Kato K, Imaizumi Y, Seto M, Ohshima K (2016) PD-L1 expression on neoplastic or stromal cells is respectively a poor or good prognostic factor for adult T-cell leukemia/lymphoma. Blood 128(10):1374–1381. https://doi.org/10.1182/blood-2016-02-698936

    Article  CAS  PubMed  Google Scholar 

  35. Ramsay AG, Clear AJ, Fatah R, Gribben JG (2012) Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood 120(7):1412–1421. https://doi.org/10.1182/blood-2012-02-411678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kim WY, Jung HY, Nam SJ, Kim TM, Heo DS, Kim CW, Jeon YK (2016) Expression of programmed cell death ligand 1 (PD-L1) in advanced stage EBV-associated extranodal NK/T cell lymphoma is associated with better prognosis. Virchows Arch 469(5):581–590. https://doi.org/10.1007/s00428-016-2011-0

    Article  CAS  PubMed  Google Scholar 

  37. Casulo C, O'Connor O, Shustov A, Fanale M, Friedberg JW, Leonard JP, Kahl BS, Little RF, Pinter-Brown L, Advani R, Horwitz S (2017) T-cell lymphoma: recent advances in characterization and new opportunities for treatment. J Natl Cancer Inst 109(2). https://doi.org/10.1093/jnci/djw248

  38. Pechloff K, Holch J, Ferch U, Schweneker M, Brunner K, Kremer M, Sparwasser T, Quintanilla-Martinez L, Zimber-Strobl U, Streubel B, Gewies A, Peschel C, Ruland J (2010) The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma. J Exp Med 207(5):1031–1044. https://doi.org/10.1084/jem.20092042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wilcox RA (2016) A three-signal model of T-cell lymphoma pathogenesis. Am J Hematol 91(1):113–122. https://doi.org/10.1002/ajh.24203

    Article  CAS  PubMed  Google Scholar 

  40. Shi J, Hou S, Fang Q, Liu X, Liu X, Qi H (2018) PD-1 controls follicular T helper cell positioning and function. Immunity 49(2):264–274 e264. https://doi.org/10.1016/j.immuni.2018.06.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the Basic Science Research Program (grant no. NRF-2016R1D1A1B01015964) through the National Research Foundation (NRF) funded by the Ministry of Education, Science and Technology (MEST), Republic of Korea.

Author information

Author notes

  1. Sehui Kim and Dohee Kwon contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea

    Sehui Kim, Dohee Kwon, Jiwon Koh, Chul Woo Kim & Yoon Kyung Jeon

  2. Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea

    Sehui Kim, Chul Woo Kim & Yoon Kyung Jeon

  3. Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea

    Soo Jeong Nam

  4. Department of Pathology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul, 07061, Republic of Korea

    Young A Kim

  5. Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea

    Tae Min Kim

Authors
  1. Sehui Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dohee Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiwon Koh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Soo Jeong Nam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Young A Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tae Min Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chul Woo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yoon Kyung Jeon
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Study concept and design were performed by Sehui Kim, Dohee Kwon, and Yoon Kyung Jeon. Material and data collection and analysis were performed by Sehui Kim, Dohee Kwon, Jiwon Koh, Soo Jeong Nam, Young A Kim, Chul Woo Kim, and Yoon Kyung Jeon. Figures and tables were made by Sehui Kim and Dohee Kwon. Clinical data collection was performed by Tae Min Kim, Dohee Kwon and Jiwon Koh. The draft of the manuscript was written by Sehui Kim, Dohee Kwon, and Yoon Kyung Jeon and all authors reviewed and commented on the manuscript and approved the final manuscript.

Corresponding author

Correspondence to Yoon Kyung Jeon.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the Institutional Review Board of Seoul National University Hospital (IRB no. 1110-111-383).

Informed consent

Informed consent for participation in the study was waived by the Institutional Review Board of Seoul National University Hospital on the basis that this study was a retrospective study using archived material, and did not increase risk to the patients.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, S., Kwon, D., Koh, J. et al. Clinicopathological features of programmed cell death-1 and programmed cell death-ligand-1 expression in the tumor cells and tumor microenvironment of angioimmunoblastic T cell lymphoma and peripheral T cell lymphoma not otherwise specified. Virchows Arch 477, 131–142 (2020). https://doi.org/10.1007/s00428-020-02790-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-020-02790-z

Keywords

Search

Navigation