Treatment Advances in EBV Related Lymphoproliferative Diseases

Abstract

Epstein Barr virus (EBV) can affect 90% of the human population. It can invade B lymphocytes, T lymphocytes and natural killer cells of the host and remain in the host for life. The long latency and reactivation of EBV can cause malignant transformation, leading to various lymphoproliferative diseases (LPDs), including EBV-related B-cell lymphoproliferative diseases (EBV-B-LPDs) (for example, Burkitt lymphoma (BL), classic Hodgkin's lymphoma (cHL), and posttransplantation and HIV-related lymphoproliferative diseases) and EBV-related T-cell lymphoproliferative diseases (EBV-T/NK-LPDs) (for example, extranodal nasal type natural killer/T-cell lymphoma (ENKTCL), aggressive NK cell leukaemia (ANKL), and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). EBV-LPDs are heterogeneous with different clinical features and prognoses. The treatment of EBV-LPDs is usually similar to that of EBV-negative lymphoma with the same histology and can include chemotherapy, radiotherapy, and hematopoietic stem cell transplant (HSCT). However, problems such as serious toxicity and drug resistance worsen the survival prognosis of patients. EBV expresses a variety of viral and lytic proteins that regulate cell cycle and death processes and promote the survival of tumour cells. Based on these characteristics, a series of treatment strategies for EBV in related malignant tumours have been developed, such as monoclonal antibodies, immune checkpoint inhibitors, cytotoxic T lymphocytes (CTLs) and epigenetic therapy. These new individualized therapies can produce highly specific killing effects on tumour cells, and nontumour cells can be protected from toxicity. This paper will focus on the latest progress in the treatment of EBV-LPDs based on pathological mechanisms.

Keywords: advances; barr virus; lymphoma; lymphoproliferative disorders; therapy.

Figure 1

EBV expresses different viral proteins in different host cells during a latent infection. Latent type 0: EBER and miRNA are expressed in the nucleus of host cells, mainly in EBV carriers in good health. Latent type I: EBNA1, EBER and miRNA are commonly expressed in patients with Burkitt lymphoma (BL) (5). Latent type II: EBNA1, EBER, miRNA, LMP1, LMP2A, and LMP2B are generally expressed in patients with HL, nasal NK/T cell lymphoma (NKTCL), NPC and diffuse large B-cell lymphoma (DLBCL) (6, 7). Latent type III: EBNA1–4, EBER, miRNA, LMP1, LMP2A and LMP2B can be expressed in posttransplant lymphoproliferative disease (PTLD), lymphoblastic cell line (LCL) and AIDS-associated B-cell lymphoma (8).

Figure 2

EBV lytic cycle reactivation. After a variety of stimulants activate the EBV Z/R promoters (Zp and Rp), the two immediate early proteins reciprocally activate expression and drive the EBV lytic cycle. In this process, a series of lytic proteins are produced to regulate gene expression and induce DNA replication. Finally, the virus particles are packaged by structural proteins and released through exocytosis.

Figure 3

Summary of the immunotherapeutic mechanism of EBV infected tumor cells. EBV infected tumor cells express PD-L1, and binding with PD-1-expressing T cells in microenvironment can inhibit immune killing function; EBV drives the overexpression of latent membrane protein LMP and the activates NF- κB/MAPK and JAK/STAT signaling pathways lead to high expression of PD-L1. Therefore, after the infusion of polyclonal EBV specific CTLs, the increased frequency of EBV and LMP specific T cells and the application of PD-1/PD-1/L1 drugs can reduce immunosuppression and kill tumour cells.