EBV Positivity and Programmed Death-ligand 1 Expression in Diffuse Large B-cell Lymphoma: A Systematic Review

Barzyk, Gabriela Anna; Sheriff, Vafie

doi:10.21873/anticanres.14616

Cited by 8 publications

(8 citation statements)

References 36 publications

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“…Moreover, it was suggested that the upregulation of PDL2 on 9p24.1 may induce immune evasion, and it was associated with poor prognosis in EBV + DLBCL [ 70 ]. The amplification of PDL1 could be involved in the increased expression of PDL1, detected by immunohistochemistry (IHC), in tumor cells in EBV + DLBCL, which was also proved to be associated with prognosis [ 54 , 81 , 82 , 83 ]. In fact, it was demonstrated that EBV − LMP1 increases PDL1 promoter and enhancer activity [ 84 ].…”

Section: Genetic Alterationsmentioning

confidence: 99%

“…Regarding EBV-associated DLBCL, strong PDL1 expression in tumor cells of patients with EBV+DLBCL was observed, suggesting a mechanism of induction of immune tolerance [ 83 ]. Nevertheless, given that PDL1 can be also expressed in immune cells at the microenvironment, PDL1 expression was also demonstrated in the TME of EBV + DLBCL cases, as a mechanism to strengthen immune exhaustion.…”

Section: Microenvironment Compositionmentioning

confidence: 99%

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Advances in the Pathogenesis of EBV-Associated Diffuse Large B Cell Lymphoma

Chabay

2021

Cancers

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Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma (NHL) in adults. Epstein–Barr virus (EBV) positive DLBCL of the elderly was defined by the World Health Organization (WHO) in 2008, it was restricted only to patients older than 50 years old, and it was attributed to immunesenescence associated with physiological aging. After the description of EBV-associated DLBCL in children and young adults, the WHO redefined the definition, leading to the substitution of the modifier “elderly” with “not otherwise specified” (EBV + DLBCL, NOS) in the updated classification, and it is no more considered provisional. The incidence of EBV + DLBCL, NOS varies around the world, in particular influenced by the percentage of EBV+ cells used as cut-off to define a case as EBV-associated. EBV has effect on the genetic composition of tumor cells, on survival, and at the recruitment of immune cells at the microenvironment. In this review, the role of EBV in the pathogenesis of DLBCL is discussed.

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Section: Genetic Alterationsmentioning

confidence: 99%

Section: Microenvironment Compositionmentioning

confidence: 99%

Advances in the Pathogenesis of EBV-Associated Diffuse Large B Cell Lymphoma

Chabay

2021

Cancers

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“…EBV-associated lymphomas have a virally mediated overexpression of PD-L1, which makes them sensitive to PD-1 blockade treatment [7]. A supplementary immunohistochemical examination with the PD-L1 SP142 clone was performed, revealing positivity in about 80% of the malignant cells (Fig.…”

Section: Case Presentationmentioning

confidence: 99%

Successful treatment of refractory retroperitoneal Epstein-Barr virus-positive diffuse large B-cell lymphoma with secondary hemophagocytic syndrome by sequential combination regimen of PD-1 blockade and chimeric antigen receptor T cells: a case report

Zhang

et al. 2021

Anti-Cancer Drugs

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Epstein-Barr virus (EBV) is convincingly contributed to the development of several types of lymphomas such as NK/T cell lymphoma, Burkitt lymphoma, plasmablastic lymphoma, and diffuse large B cell lymphoma (DLBCL). Herein, we reported an atypical case of EBV-positive DLBCL in an immunocompetent young male patient who presented with epistaxis due to hypergammaglobulinemia. 2-Deoxy-2-[fluorine-8] fluoro-d-glucose PET/computed tomography showed multiple highly metabolic retroperitoneal tissue masses with the involvement of bilateral adrenal gland. Ultrasonography-guided biopsy revealed a significant number of lymphocytes and plasma-like cells that are immunopositive for plasmacell markers and partly positive for pan-B cell markers. The Ki-67 proliferation index was 20%. The extensive distribution of EBV-encoded small RNAs was confirmed by in-situ hybridization. Due to atypical/overlapping pathological characteristics, it was initially misdiagnosed as extramedullary plasmacytoma and treated with two cycles of bortezomib, lenalidomide, and dexamethasone. Disease progression occurred and pathology consultation for the retroperitoneal biopsies modified the diagnosis to EBV-positive DLBCL with plasma cell differentiation. The treatment was adjusted to etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab, and lenalidomide (R2-EPOCH), but no response was observed after three cycles of treatment and he developed hemophagocytic syndrome during treatment. A monotherapy of anti-programmed cell death-1 (PD-1) treatment with tiririzumab was administered, successfully controlling hemophagocytic syndrome and EBV infection. The response assessment was partial for EBV-positive DLBCL, subsequent anti-CD19 chimeric antigen receptor-T (CAR-T) cell therapy resulted in complete remission including lumps, immunoglobulins, and negative EBV-DNA 1.5 months later. The present case study proved the possibility of PD-1 blockade in controlling EBV infection and associated hemophagocytic syndrome and offered an example of the combination of CAR-T therapy and PD-1 blockade for refractory EBV-positive DLBCL in clinic. Anti-Cancer Drugs 33: e769-e775

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“…12,13 EBV induces PD-L1 expression through viral antigens, including LMP1 and EBNA2, whereas in non-Hodgkin lymphomas, the association between PD-L1 expression and EBV infection remains controversial. 14 This may be partly because of the intratumoral heterogeneous expression of PD-L1 and different cutoffs used to assess PD-L1 positivity. Furthermore, no study has directly compared PD-L1 expression with EBV antigen expression patterns at single-cell resolution in clinical samples.…”

mentioning

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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EBV Positivity and Programmed Death-ligand 1 Expression in Diffuse Large B-cell Lymphoma: A Systematic Review

Cited by 8 publications

References 36 publications

Advances in the Pathogenesis of EBV-Associated Diffuse Large B Cell Lymphoma

Advances in the Pathogenesis of EBV-Associated Diffuse Large B Cell Lymphoma

Successful treatment of refractory retroperitoneal Epstein-Barr virus-positive diffuse large B-cell lymphoma with secondary hemophagocytic syndrome by sequential combination regimen of PD-1 blockade and chimeric antigen receptor T cells: a case report

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

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