Clinicopathological evaluation of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in post-transplant lymphoproliferative disorders: association with Epstein-Barr virus, PD-L1 copy number alterations, and outcome

doi:10.1111/his.13857

. 2019 Dec;75(6):799-812.

doi: 10.1111/his.13857. Epub 2019 Oct 6.

Clinicopathological evaluation of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in post-transplant lymphoproliferative disorders: association with Epstein-Barr virus, PD-L1 copy number alterations, and outcome

Luis Veloza¹, Cristina Teixido¹, Natalia Castrejon¹, Fina Climent², Ana Carrió¹, Marta Marginet¹, Davide Soldini³, Blanca González-Farré¹, Inmaculada Ribera-Cortada^{1

4}, Armando Lopez-Guillermo⁵, Eva González-Barca⁶, Adriana Sierra¹, Mileyka Herrera⁷, Cándida Gómez¹, Adriana Garcia¹, Olga Balagué¹, Elias Campo¹, Antonio Martinez¹

Affiliations

¹ Department of Pathology, Hospital Clinic, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
² Department of Pathology, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain.
³ Institut für klinische Pathologie medica, Zürich, Switzerland.
⁴ Department of Pathology, Hospital Nostra Senyora de Meritxell, Escaldes-Engordany, Principat d'Andorra.
⁵ Department of Haematology, Hospital Clinic, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
⁶ Department of Clinical Haematology, Institut Català Oncologia (ICO)-Hospitalet, IDIBELL, Barcelona, Spain.
⁷ Fachbereich Pathologie, Vivantes Klinikum Neukölln, Berlin, Germany.

PMID: 30861172
DOI: 10.1111/his.13857

Clinicopathological evaluation of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in post-transplant lymphoproliferative disorders: association with Epstein-Barr virus, PD-L1 copy number alterations, and outcome

Luis Veloza et al. Histopathology. 2019 Dec.

. 2019 Dec;75(6):799-812.

doi: 10.1111/his.13857. Epub 2019 Oct 6.

Authors

Affiliations

¹ Department of Pathology, Hospital Clinic, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
² Department of Pathology, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain.
³ Institut für klinische Pathologie medica, Zürich, Switzerland.
⁴ Department of Pathology, Hospital Nostra Senyora de Meritxell, Escaldes-Engordany, Principat d'Andorra.
⁵ Department of Haematology, Hospital Clinic, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
⁶ Department of Clinical Haematology, Institut Català Oncologia (ICO)-Hospitalet, IDIBELL, Barcelona, Spain.
⁷ Fachbereich Pathologie, Vivantes Klinikum Neukölln, Berlin, Germany.

PMID: 30861172
DOI: 10.1111/his.13857

Abstract

Aims: The clinical implications of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in patients with post-transplant lymphoproliferative disorders are largely unknown, and its association with Epstein-Barr virus (EBV) status and PD-L1 copy number alterations (CNAs) has not been thoroughly studied.

Methods and results: PD1/PD-L1 expression was studied in 50 adult post-transplant lymphoproliferative disorders, and the correlations with PD-L1 CNAs, EBV, clinicopathological features and outcome were evaluated. Thirty-seven (74%) cases were classified as diffuse large B-cell lymphoma (DLBCL), nine (18%) cases were classified as polymorphic, and four (8%) cases were classified as classic Hodgkin lymphoma. Thirty-four cases were EBV-positive, with 29 of 34 (85%) having latency II or III, and 15 of 34 (44%) having viral replication. PD-L1 expression in tumour cells and tumour-associated macrophages was observed in 30 (60%) and 37 (74%) cases, respectively. PD1 positivity was seen in 16 (32%) cases. PD-L1 expression was associated with EBV with latency II or III (P = 0.001) and organ rejection (P = 0.04), and, in DLBCL, with non-germinal centre type DLBCL (P < 0.001). Cases with PD-L1-positive tumour cells showed a higher number of PD-L1 CNAs than PD-L1-negative cases (P = 0.001). Patients with EBV/latency III/replication and simultaneous PD-L1 expression showed the worst overall survival (P < 0.001).

Conclusions: The PD1/PD-L1 axis is deregulated in post-transplant lymphoproliferative disorders, with frequent PD-L1 expression and PD1 negativity. PD-L1 expression is associated with EBV latency II or III and PD-L1 CNAs, and probably reflects a proinflammatory tumour microenvironment. The combined analysis of EBV status and PD-L1 expression may help to identify deeply immunosuppressed patients who can benefit from immune reconstitution approaches.

Keywords: Epstein-Barr virus; FISH; PD-L1; PD1; diffuse large B-cell lymphoma; post-transplant lymphoproliferative disorders; prognosis.

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References

1. Swerdlow SH, Webber SA, Chadburn A et al. Post-transplant lymphoproliferative disorders. In Swerdlow SH, Campo E, Harris NL eds. World Health Organization classification of tumours of haematopoietic and lymphoid tissues, revised 4th ed. Lyon: IARC Press, 2017; 453-462.
1. Parker A, Bowles K, Bradley JA et al. Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients-BCSH and BTS Guidelines. Br. J. Haematol. 2010; 149; 693-705.
1. Keir ME, Butte MJ, Freeman GJ et al. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 2008; 26; 677-704.
1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012; 12; 252-264.
1. Ishida M, Iwai Y, Tanaka Y et al. Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues. Immunol. Lett. 2002; 84; 57-62.

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[1] Swerdlow SH, Webber SA, Chadburn A et al. Post-transplant lymphoproliferative disorders. In Swerdlow SH, Campo E, Harris NL eds. World Health Organization classification of tumours of haematopoietic and lymphoid tissues, revised 4th ed. Lyon: IARC Press, 2017; 453-462.

[2] Swerdlow SH, Webber SA, Chadburn A et al. Post-transplant lymphoproliferative disorders. In Swerdlow SH, Campo E, Harris NL eds. World Health Organization classification of tumours of haematopoietic and lymphoid tissues, revised 4th ed. Lyon: IARC Press, 2017; 453-462.

[3] Parker A, Bowles K, Bradley JA et al. Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients-BCSH and BTS Guidelines. Br. J. Haematol. 2010; 149; 693-705.

[4] Parker A, Bowles K, Bradley JA et al. Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients-BCSH and BTS Guidelines. Br. J. Haematol. 2010; 149; 693-705.

[5] Keir ME, Butte MJ, Freeman GJ et al. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 2008; 26; 677-704.

[6] Keir ME, Butte MJ, Freeman GJ et al. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 2008; 26; 677-704.

[7] Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012; 12; 252-264.

[8] Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012; 12; 252-264.

[9] Ishida M, Iwai Y, Tanaka Y et al. Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues. Immunol. Lett. 2002; 84; 57-62.

[10] Ishida M, Iwai Y, Tanaka Y et al. Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues. Immunol. Lett. 2002; 84; 57-62.

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Clinicopathological evaluation of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in post-transplant lymphoproliferative disorders: association with Epstein-Barr virus, PD-L1 copy number alterations, and outcome

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Clinicopathological evaluation of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in post-transplant lymphoproliferative disorders: association with Epstein-Barr virus, PD-L1 copy number alterations, and outcome

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