EBV-positive B-cell Lymphomas and Lymphoproliferative Disorders: Review from the Perspective of Immune Escape and Immunodeficiency

Overview

Journal Cancer Med

Specialty Oncology

Date 2021 Aug 13

PMID 34387382

Citations 20

Authors

Akira Satou

Shigeo Nakamura

Affiliations

Soon will be listed here.

Abstract

Background: Epstein-Barr virus (EBV) is detected in a variety of B-cell lymphomas (BCLs) and B-cell lymphoproliferative disorders (B-LPDs). Immunodeficiency has been considered to play a key role in the pathogenesis of these diseases. In addition, immune escape of tumor cells may also contribute to the development of EBV BCLs and B-LPDs. The PD-1/PD-L1 pathway is particularly important for immune escape of tumor cells that contribute to development of lymphoma through suppression of cytotoxic T-cell function. We now consider PD-L1 immunohistochemistry (IHC) a very useful method for predicting whether tumor cells of lymphoid malignancies are characterized by the immune escape mechanism.

Methods: We reviewed articles of EBV BCLs and B-LPDs from the perspective of immune escape and immunodeficiency, particularly focusing on PD-L1 IHC.

Results: Based on PD-L1 IHC, we consider that EBV BCL and B-LPD can be classified into three types: "immunodeficiency", "immune escape", and "immunodeficiency + immune escape" type. The immunodeficiency type includes EBV diffuse large BCL (DLBCL) of the elderly, EBV sporadic Burkitt lymphoma, EBV mucocutaneous ulcer, and methotrexate (MTX)-associated B-LPD. The immune escape type includes EBV classic Hodgkin lymphoma (CHL) and EBV DLBCL of the young. The immunodeficiency + immune escape type includes CHL type MTX-associated LPD and a minor subset of EBV DLBCL of the elderly.

Conclusions: Recently, good results have been reported for immune check-point inhibitors in treating lymphoma. Lymphomas and LPDs characterized by immune escape are regarded as good candidates for PD1/PD-L1 blockade therapy. Therefore, from both the clinical and pathological perspective, we suggest that lymphoma diagnosis should be made considering immune escape and immunodeficiency.

Citing Articles

Primary Cutaneous Methotrexate-Associated T-Cell Lymphoproliferative Disorder in the Setting of Autoimmune Disease: A Case Series and Review of the Literature.

Nocco S, Magro C Am J Dermatopathol. 2025; 47(2):145-152.

PMID: 39851907 PMC: 11776889. DOI: 10.1097/DAD.0000000000002905.

Advances in multimodal imaging for adrenal gland disorders: integrating CT, MRI, and nuclear medicine.

Yokoyama K, Matsuki M, Isozaki T, Ito K, Imokawa T, Ozawa A Jpn J Radiol. 2025; .

PMID: 39794659 DOI: 10.1007/s11604-025-01732-6.

A case of gastric/duodenal diffuse large B cell lymphoma observed during the administration of tacrolimus/azathioprine for dermatomyositis.

Yamamoto A, Ito A, Nakamura S, Higuchi T, Harigai M, Shinohara A Clin J Gastroenterol. 2024; 18(1):67-73.

PMID: 39638937 DOI: 10.1007/s12328-024-02077-9.

Hemophagocytic lymphohistiocytosis in a patient with Epstein-Barr virus-positive diffuse large B-cell lymphoma treated with chimeric antigen receptor T-cell therapy.

Meireles A, Iacoboni G, Moco L, Ramos I, Bras G, Azevedo J Immunotherapy. 2024; 16(18-19):1105-1111.

PMID: 39417342 PMC: 11633410. DOI: 10.1080/1750743X.2024.2409622.

SLC27A2 is a potential immune biomarker for hematological tumors and significantly regulates the cell cycle progression of diffuse large B-cell lymphoma.

Wang Y, Chen X, Li Y, Zhang Z, Xia L, Jiang J BMC Med Genomics. 2024; 17(1):105.

PMID: 38664735 PMC: 11046844. DOI: 10.1186/s12920-024-01853-3.

References

Topalian S, Taube J, Anders R, Pardoll D . Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016; 16(5):275-87. PMC: 5381938. DOI: 10.1038/nrc.2016.36. View

Gion Y, Iwaki N, Takata K, Takeuchi M, Nishida K, Orita Y . Clinicopathological analysis of methotrexate-associated lymphoproliferative disorders: Comparison of diffuse large B-cell lymphoma and classical Hodgkin lymphoma types. Cancer Sci. 2017; 108(6):1271-1280. PMC: 5480080. DOI: 10.1111/cas.13249. View

Ikeda T, Gion Y, Sakamoto M, Tachibana T, Nishikori A, Nishimura M . Clinicopathological analysis of 34 Japanese patients with EBV-positive mucocutaneous ulcer. Mod Pathol. 2020; 33(12):2437-2448. DOI: 10.1038/s41379-020-0599-8. View

Connors J, Cozen W, Steidl C, Carbone A, Hoppe R, Flechtner H . Hodgkin lymphoma. Nat Rev Dis Primers. 2020; 6(1):61. DOI: 10.1038/s41572-020-0189-6. View

Parsa A, Waldron J, Panner A, Crane C, Parney I, Barry J . Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2006; 13(1):84-8. DOI: 10.1038/nm1517. View

Ansell S, Lesokhin A, Borrello I, Halwani A, Scott E, Gutierrez M . PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2014; 372(4):311-9. PMC: 4348009. DOI: 10.1056/NEJMoa1411087. View

Green M, Rodig S, Juszczynski P, Ouyang J, Sinha P, ODonnell E . Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012; 18(6):1611-8. PMC: 3321508. DOI: 10.1158/1078-0432.CCR-11-1942. View

Marzec M, Zhang Q, Goradia A, Raghunath P, Liu X, Paessler M . Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci U S A. 2008; 105(52):20852-7. PMC: 2634900. DOI: 10.1073/pnas.0810958105. View

Rath T, Rubbert A . Drug combinations with methotrexate to treat rheumatoid arthritis. Clin Exp Rheumatol. 2010; 28(5 Suppl 61):S52-7. View

10.

Schreiber R, Old L, Smyth M . Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011; 331(6024):1565-70. DOI: 10.1126/science.1203486. View

11.

Topalian S, Drake C, Pardoll D . Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015; 27(4):450-61. PMC: 4400238. DOI: 10.1016/j.ccell.2015.03.001. View

12.

Nicolae A, Pittaluga S, Abdullah S, Steinberg S, Pham T, Davies-Hill T . EBV-positive large B-cell lymphomas in young patients: a nodal lymphoma with evidence for a tolerogenic immune environment. Blood. 2015; 126(7):863-72. PMC: 4536540. DOI: 10.1182/blood-2015-02-630632. View

13.

Younes A, Santoro A, Shipp M, Zinzani P, Timmerman J, Ansell S . Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016; 17(9):1283-94. PMC: 5541855. DOI: 10.1016/S1470-2045(16)30167-X. View

14.

Ok C, Papathomas T, Medeiros L, Young K . EBV-positive diffuse large B-cell lymphoma of the elderly. Blood. 2013; 122(3):328-40. PMC: 3779382. DOI: 10.1182/blood-2013-03-489708. View

15.

Dojcinov S, Venkataraman G, Raffeld M, Pittaluga S, Jaffe E . EBV positive mucocutaneous ulcer--a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol. 2010; 34(3):405-17. PMC: 6437677. DOI: 10.1097/PAS.0b013e3181cf8622. View

16.

Wessels J, Huizinga T, Guchelaar H . Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology (Oxford). 2007; 47(3):249-55. DOI: 10.1093/rheumatology/kem279. View

17.

Bunn B, van Heerden W . EBV-positive mucocutaneous ulcer of the oral cavity associated with HIV/AIDS. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015; 120(6):725-32. DOI: 10.1016/j.oooo.2015.06.028. View

18.

Oyama T, Yamamoto K, Asano N, Oshiro A, Suzuki R, Kagami Y . Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients. Clin Cancer Res. 2007; 13(17):5124-32. DOI: 10.1158/1078-0432.CCR-06-2823. View

19.

Shimoyama Y, Yamamoto K, Asano N, Oyama T, Kinoshita T, Nakamura S . Age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorders: special references to lymphomas surrounding this newly recognized clinicopathologic disease. Cancer Sci. 2008; 99(6):1085-91. PMC: 11159301. DOI: 10.1111/j.1349-7006.2008.00813.x. View

20.

Lesokhin A, Ansell S, Armand P, Scott E, Halwani A, Gutierrez M . Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol. 2016; 34(23):2698-704. PMC: 5019749. DOI: 10.1200/JCO.2015.65.9789. View