Abstract:

Epstein-Barr virus (EBV) can be latent in resting memory or naive B lymphocytes for a long time in affected people. Aging-induced immunosenescence is associated with an increased risk of EBV-related malignancies in EBV-infected patients. EBV positive diffuse large B-cell lymphoma, not otherwise specified (EBV⁺DLBCL-NOS) is identified as occurring in large B-cell lymphoma with no known history of immunodeficiency disease or lymphoma and whose tumor nuclei expressed EBV encoded RNA (EBER). The prevalence of EBV⁺DLBCL-NOS is significantly higher in Asia and Latin America than in other regions worldwide, and it mainly affects patients aged 50 years or older. EBV⁺DLBCL-NOS patients are associated with a more aggressive clinical course, a more advanced disease, and a higher rate of extra-nodal involvement (more than 80%) compared with EBV negative DLBCL (EBV^-DLBCL) patients. The elderly patients with EBV⁺DLBCL-NOS have poorer overall survival and progression-free survival than young adults. Rituximab-containing immunochemotherapy significantly improves the prognosis of patients with EBV^-DLBCL, however, the optimal first-line treatment for EBV⁺DLBCL-NOS still needs to be further explored. The current understanding of EBV⁺DLBCL-NOS, a rare subtype of DLBCL, is very limited because of the relatively low incidence of EBV⁺DLBCL-NOS with a regional difference, as well as lacking high-quality clinical study. However, the DLBCL field is changing rapidly with new technologies, such as next-generation sequencing. To date, few studies have reported that multiple cells signaling pathways are aberrantly activated in tumor cells of EBV⁺DLBCL-NOS, such as nuclear factor-κB (NF-κB) and Janus kinase/signal transducer and activator of transcription (JAK/STAT). In addition, abnormalities in immune processes have been observed in tumor cells of EBV⁺DLBCL-NOS, such as the response to interferon, the antigen presentation system, and immune checkpoint molecules. The discovery of these basic research findings fosters the identification of relevant therapeutic targets and facilitates the exploration of novel therapeutic strategies. In the future, the benefits of immunotherapy, targeted therapy, and chimeric antigen receptor T-cell (CAR-T) therapy for EBV⁺DLBCL-NOS patients remain unknown and require extensive research.

Key words: Epstein-Barr virus, Non-Hodgkin’s lymphoma, Diffuse large B-cell lymphoma, Immunotherapy, Targeted therapy