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

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.

HHV8-positive, EBV-positive Hodgkin lymphoma-like large B cell lymphoma: expanding the spectrum of HHV8 and EBV-associated lymphoproliferative disorders

“…PD-L1/PD1 expression and the presence of PD-L1 CNAs in our case may suggest a role of immunomodulation, which has been associated with EBV in different lymphomas, including Hodgkin lymphoma and LPDs developed in the setting of immunodeficiencies [10,15]. PD-L1 expression has also been reported in 50% of cases of PEL [15].…”

“…Since tumor cells expressed PD-L1, a FISH study to detect PD-L1 copy number alterations (CNAs) was performed in the 2017 biopsy, as previously described [10]. Interestingly, we observed disperse atypical large (Fig.…”

“…1j). EBV Latency and viral replication studies showed an EBV latency pattern I without viral replication (LMP1−, EBNA2−, ZEBRA−) [10].…”

EBV microRNA-BHRF1-2-5p targets the 3′UTR of immune checkpoint ligands PD-L1 and PD-L2

“…14 This translates into increased tumor cell surface expression of PD-L1 protein, with high frequency of PD-L1 overexpression in EBV 1 DLBCL and EBV 1 PTLD, associated with EBV latency 2 and 3 and non-GCB COO subtype DLBCL. 61,62 Analysis of human EBV 1 DLBCL biopsies indicate that the antigen-presenting machinery is typically intact, and polymorphisms in functionally defined CD8 1 T-cell epitope-encoding regions are rare, 63 making this an attractive immunotherapy target. 5 In vitro experiments indicate that PD-1 blockade is more effective in inducing antitumor immunity in EBV 1 DLBCL than DLBCL NOS, 64 and PD-1 blockade inhibits EBV 1 lymphoma in humanized mice.…”

Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disorders after Hematopoietic Stem Cell Transplantation: Pathogenesis, Risk Factors and Clinical Outcomes

“…Most results are based on in vitro data, and further evaluation (in prospective clinical trials if possible) is necessary before such agents can be used as a treatment for patients with PTLD. As described above, EBV positivity is associated with copy number alterations and increased expression of PDL1 and PDL2 [31,124]. Immune checkpoint inhibitors have potential efficacy against EBV-positive PTLD by inducing T-cell immunity, and a phase II trial is ongoing (NCT03258567) [125].…”