Programmed cell death-ligand 1 (PD-L1)+ tumour cells and low-reacting programmed cell death 1 (PD1)+ tumour-infiltrating lymphocytes predict poor prognosis in Epstein–Barr virus+ diffuse large B-cell lymphoma

Kimura, Shoichi; Oshiro, Yumi; Iwasaki, Hiromi; Kadowaki, Masanori; Mihashi, Yasuhito; Sakata, Toshifumi; Kawauchi, Shigeto; Ziyao, Wang; Takamatsu, Yasushi; Takeshita, Morishige

doi:10.1007/s10238-021-00754-4

Cited by 4 publications

(7 citation statements)

References 28 publications

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“…28 However, a second Japanese study reported a higher prevalence of PD-L1 expression ($40%) in EBV+ DLBCL, which was associated with poor outcome while CD30, BCL2, MYC, and p53 expression were not associated with survival. 29 Survivin affects cellular apoptosis through indirect mechanisms that lead to inhibition of caspase 9. 69 In DLBCL treated with R-CHOP, high expression of survivin in tumor cells was associated with poor outcomes.…”

Section: Novel Pathological and Molecular Markers Have Been Associatedmentioning

confidence: 99%

“…A Japanese study showed that PD‐L1 was infrequently (~10%) expressed in EBV+ DLBCL but was associated with a shorter progression‐free survival, though OS was not statistically different 28 . However, a second Japanese study reported a higher prevalence of PD‐L1 expression (~40%) in EBV+ DLBCL, which was associated with poor outcome while CD30, BCL2, MYC, and p53 expression were not associated with survival 29 . Survivin affects cellular apoptosis through indirect mechanisms that lead to inhibition of caspase 9 69 .…”

Section: Other Prognostic Factorsmentioning

confidence: 99%

“…26,27 CD30 and PDL-1 (threshold of 5% of the neoplastic cells) may be positive in up to 90% of the cases (Figure 2F). 25,28,29 The genetic and molecular landscape of EBV+ DLBCL, NOS is heterogeneous, but consistent monoclonal IGH gene rearrangement is present in the majority of the cases. 30,31 The evaluation of miRNA profile in this entity revealed potential pathogenic role of miR-BHRF1-2-5p, miR-BHRF1-3-5p, miR-BART2, and miR-BART13.…”

Section: Diagnosismentioning

confidence: 99%

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EBV‐positive diffuse large B‐cell lymphoma, not otherwise specified: 2022 update on diagnosis, risk‐stratification, and management

et al. 2022

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Disease Overview Epstein Barr virus‐positive (EBV+) diffuse large B‐cell lymphoma (DLBCL), not otherwise specified (NOS) is an entity included in the WHO classification of lymphoid neoplasms since 2016. EBV+ DLBCL, NOS, is an aggressive B‐cell lymphoma associated with EBV infection, and a poor prognosis with standard chemotherapeutic approaches. Diagnosis The diagnosis is made through a careful pathological evaluation. Detection of EBV‐encoded RNA (EBER) is considered standard for diagnosis; however, a clear cutoff for percentage of positive cells has not been defined. The differential diagnosis includes plasmablastic lymphoma (PBL), DLBCL associated with chronic inflammation, primary effusion lymphoma (PEL), among others. Risk‐Stratification The International Prognostic Index (IPI) and the Oyama score can be used for risk‐stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 and PD‐1/PD‐L1 are emerging as potential adverse but targetable biomarkers. Management Patients with EBV+ DLBCL, NOS, should be staged and managed following similar guidelines than patients with EBV‐negative DLBCL. EBV+ DLBCL, NOS, however, might have a worse prognosis than EBV‐negative DLBCL in the era of chemoimmunotherapy. Therefore, the inclusion of patients in clinical trials when available is recommended. There is an opportunity to study and develop targeted therapy in the management of patients with EBV+ DLBCL, NOS.

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Section: Novel Pathological and Molecular Markers Have Been Associatedmentioning

confidence: 99%

Section: Other Prognostic Factorsmentioning

confidence: 99%

Section: Diagnosismentioning

confidence: 99%

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EBV‐positive diffuse large B‐cell lymphoma, not otherwise specified: 2022 update on diagnosis, risk‐stratification, and management

et al. 2022

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“…Antigen persistence leads to ongoing PD-1 expression and eventual T-cell exhaustion (19). In EBV+ DLBCL patients, the expression of a few reactive PD1+ TILs was described (20). In line with this, it was suggested that viral LMP1 oncoprotein may sustain an immunosuppressive microenvironment by the induction of immunosuppressive cytokines and the expression of PD-1 (21).…”

Section: Discussionmentioning

confidence: 88%

PD-1 and LAG-3 expression in EBV-associated pediatric Hodgkin lymphoma has influence on survival

et al. 2022

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In pediatric Hodgkin lymphoma (HL), the inability of the cytotoxic microenvironment induced by EBV presence to eliminate tumor cells could reflect the fact that the virus might be able to induce the expression of exhaustion markers to evade an immune response. Therefore, the expression of exhaustion markers in pediatric EBV–associated HL was evaluated. A balance between cytotoxic GrB and Th1 Tbet markers with regulatory Foxp3 was proved in EBV+ cases. In addition, exclusively in EBV-associated cHL, a correlation between PD-1 and LAG-3 expression was observed. Furthermore, those cases also displayed a trend to worse survival when they expressed LAG-3 and inferior event-free survival when both PD-1 and LAG-3 molecules were present. Therefore, even though a cytotoxic and inflammatory environment was supposed to be triggered by EBV presence in pediatric cHL, it seems that the virus may also induce the synergic effect of inhibitory molecules LAG-3 and PD-1 in this series. These observations may reflect the fact that the permissive and exhausted immune microenvironment succeeds to induce lymphomagenesis.

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“…While there have been many studies on PD-L1 expression in CHLs, non-Hodgkin lymphomas, and other LPDs, most studies have focused on a single tumor type, and the number of studies that included 2 or more tumor types is limited. 14,[18][19][20][21][22][23][24] Furthermore, the antibodies and cut offs for the evaluation of PD-L1 expression differ among studies, making it difficult to compare their results. The present study included different types of EBV-associated malignant lymphomas/LPDs with the same IHC and scoring methods, which enabled direct comparison of PD-L1 expression among different tumor types.…”

Section: Discussionmentioning

confidence: 99%

Enhanced PD-L1 Expression in LMP1-positive Cells of Epstein-Barr Virus–associated Malignant Lymphomas and Lymphoproliferative Disorders

Kume

Shinozaki‐Ushiku

Kunita

et al. 2022

American Journal of Surgical Pathology

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Epstein-Barr virus (EBV) is associated with various types of human malignancies and with programmed death ligand (PD-L) 1 expression in neoplastic cells. However, in EBV-associated malignant lymphomas and lymphoproliferative disorders (LPDs), there is limited information regarding PD-L1 expression profiles among different histologic types and patterns of EBV latency. First, we investigated PD-L1 and EBV latent gene expression using conventional immunohistochemistry and in situ hybridization in 42 EBV-associated malignant lymphomas and LPDs. Classic Hodgkin lymphoma showed the highest PD-L1 expression with diffuse expression in all cases, followed by diffuse large B-cell lymphoma/Burkitt lymphoma, LPDs, and extranodal NK/T-cell lymphoma. EBV latency at the case level was not associated with PD-L1 expression. We further evaluated the expression of PD-L1 and EBV latent genes in tumor cells at single-cell resolution using multiplex fluorescence imaging. This analysis revealed that positivity rates of latent membrane protein (LMP) 1 in tumor cells were 1.0% to 89.5% (mean 35.4%) in latency type II/III cases, and LMP1 + cells showed more frequent PD-L1 expression than LMP1 − cells (P < 0.0001, paired t test). In contrast, no association was observed between EBV nuclear antigen 2 and PD-L1 expression. Notably, tumor cells exhibiting Hodgkin/Reed-Sternberg cell-like morphology co-expressed PD-L1 and LMP1 more often than those that do not. Our observations suggested that LMP1 upregulates PD-L1 expression and is a potential biomarker for predicting the efficacy of immune checkpoint inhibitors. In addition, the heterogeneous expression of PD-L1 and EBV latent genes may produce diverse tumor cells with different oncogenic and immuneevasive properties, leading to resistance to targeted therapies.

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Programmed cell death-ligand 1 (PD-L1)+ tumour cells and low-reacting programmed cell death 1 (PD1)+ tumour-infiltrating lymphocytes predict poor prognosis in Epstein–Barr virus+ diffuse large B-cell lymphoma

Cited by 4 publications

References 28 publications

EBV‐positive diffuse large B‐cell lymphoma, not otherwise specified: 2022 update on diagnosis, risk‐stratification, and management

EBV‐positive diffuse large B‐cell lymphoma, not otherwise specified: 2022 update on diagnosis, risk‐stratification, and management

PD-1 and LAG-3 expression in EBV-associated pediatric Hodgkin lymphoma has influence on survival

Enhanced PD-L1 Expression in LMP1-positive Cells of Epstein-Barr Virus–associated Malignant Lymphomas and Lymphoproliferative Disorders

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