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

Histopathology. 2019 Dec;75(6):799-812. doi: 10.1111/his.13857. Epub 2019 Oct 6.

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.

MeSH terms

  • Adult
  • Aged
  • Apoptosis
  • B7-H1 Antigen / metabolism*
  • DNA Copy Number Variations*
  • Epstein-Barr Virus Infections / diagnosis
  • Epstein-Barr Virus Infections / mortality
  • Epstein-Barr Virus Infections / pathology*
  • Epstein-Barr Virus Infections / virology
  • Female
  • Herpesvirus 4, Human / isolation & purification*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Lymphoproliferative Disorders / diagnosis
  • Lymphoproliferative Disorders / mortality
  • Lymphoproliferative Disorders / pathology*
  • Lymphoproliferative Disorders / virology
  • Male
  • Middle Aged
  • Prognosis
  • Programmed Cell Death 1 Receptor / metabolism*

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor