Programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and EBV-encoded RNA (EBER) expression in Hodgkin lymphoma

Abstract

Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are new targets in cancer immunotherapy. PD-1 protein is an immune checkpoint expressed in many tumors. Epstein-Barr virus (EBV) is present in malignant Hodgkin/Reed-Sternberg (HRS) cells in approximately 40-50 % of Hodgkin lymphoma (HL). The aim of this study is to evaluate the clinical and prognostic importance of PD-1 and/or PD-L1 in HL and also to determine the association between EBV-encoded RNA (EBER) and PD-1/PD-L1. Formalin-fixed, paraffin-embedded tissue samples from 87 cases with HL were analyzed in this study. Immunohistochemical staining was performed to detect the PD-1 and PD-L1 expressions. Chromogenic in situ hybridization for EBER was performed using fluorescein-labeled oligonucleotide probes. PD-1 and PD-L1 expressions were found in 20 % of the cases. The EBER positivity was found in 40 cases (45 %). It has been found that co-expression of PD-1 and PD-L1 was associated with shorter survival although PD-1 or PD-L1 expressions were not found to be related with survival. Overall survival (OS) and disease-free survival (DFS) in cases without PD-1 and PD-L1 expressions were 135 and 107 months, respectively. OS and DFS in cases with co-expression for PD-1 and PD-L1 were 24 and 20 months, respectively, and these differences were found to be statistically significant for both OS and DFS (p = 0.002 and p = 0.003, respectively). Cox regression analysis showed that co-expression of PD-1 and PD-L1 was found to be an independent risk factor for prognosis (OR 6.9, 95 % CI 1.9-24.3). Targeting PD-1 and/or PD-L1 is meaningful due to the 20 % expression of each in HL, and we did not find an important association between PD-1 and PD-L1 and EBER expression in HL. Very poor outcome in cases with co-expression of PD-1/PD-L1 suggests new avenues to detect the new prognostic markers and also therapeutic approaches in HL.

Catching up with solid tumor oncology: what is the evidence for a prognostic role of programmed cell death-ligand 1/programmed cell death-1 expression in B-cell lymphomas?

“…A more recent study reported PD-L1 positivity in only 20% of examined HL patients, with staining intensities and patterns not further specified. 68 In contrast with findings in DLBCL, PD-L1 expression is not increased in EBV + patients. 35,68,70 RS cells and variants appear to lack PD-1 expression, suggesting a potentially mutually exclusive expression pattern with PD-L1.…”

“…Another study found median OS and disease-free survival (DFS) to be shorter in patients with PD-1 compared to those without PD-1 expression, as well as in patients with PD-L1 expression compared to those without, but none of these differences were statistically significant. 68 Interestingly, co-expression of PD-1 and PD-L1 emerged as an independent risk factor for prognosis (OR 6.9, 95 % CI 1.9-24.3), and both OS and DFS were significantly reduced among patients with PD-1/PD-L1 coexpression compared to both PD-1 and PD-L1 negative patients. Koh et al reported that patients with tumor PD-L1 expression were more likely to have a low level of lactate dehydrogenase (P=0.024) than PD-L1-negative patients, but neither PD-L1 nor PD-L2 expression were significantly associated with OS (P=0.477 and P=0.676) 69 (Table 6).…”

“…[64][65][66][67] PD-L1 expression on malignant cells has been described by several studies for the majority of PMBCL patients and on Reed-Sternberg (RS) cells in patients with HL, mostly in conjunction with PD-L2 [33][34][35]37,[68][69][70] (Table 5). Expression seems to differ with histological subtype, with strong tumor PD-L1 expression in the majority of patients with nodular sclerosis classical HL (cHL), mixed cellularity cHL and cHL-not otherwise specified (NOS), but only in a small fraction of nodular lymphocyte-predominant HL patients.…”

High proportions of PD-1+ and PD-L1+ leukocytes in classical Hodgkin lymphoma microenvironment are associated with inferior outcome

“…10 Previous studies have indicated that high leukocyte PD-1 expression may be associated with inferior overall survival (OS). [11][12][13][14] However, in only 1 of these did PD-1 remain associated with poorer OS after adjustment for parameters included in the IPS. 11 In 1 study, high PD-L1 expression (on either HRS cells or leukocytes) was associated with inferior OS when coexpressed with high PD-1.…”

“…11 In 1 study, high PD-L1 expression (on either HRS cells or leukocytes) was associated with inferior OS when coexpressed with high PD-1. 13 9p24.1 gene amplifications and expression of PD-1 ligands on HRS cells were associated with inferior prognosis in 1 study. 8 In contrast, 2 other studies found PD-1 ligand expression on HRS cells to have no prognostic impact.…”