Epstein-Barr Virus-Positive Natural Killer/T-Cell Lymphoma

Abstract

Extranodal natural killer/T-cell lymphoma, nasal type (ENKL), is a rare malignancy of Non-Hodgkin lymphoma characterized by an aggressive clinical course and poor prognosis. It shows strong association with Epstein-Barr virus infection and occurs more commonly in Asia and Latin America. Various genetic alterations have been identified in ENKL by gene expression profiling and sequencing techniques. The frequent deletion of chromosome 6q21 was reported to lead to the silence of several tumor suppressor genes. Also, there have been novel genetic mutations that were recently uncovered and were found to frequently activate several oncogenic pathways, including the JAK/STAT, NF-κB, and MAPK pathways. Besides, we believe that deregulated single genes and epigenetic dysregulation might be relevant to the mechanism of this disease and thus, may have the potential to shed lights on the development of new therapeutic strategies. The consensus on the standard treatment for ENKL has not yet been currently established. For localized ENKL patients, radiotherapy with concurrent chemotherapy and sequential patterns of chemotherapy and radiotherapy are recommended as first-line therapy. As for advanced or relapsed/refractory ENKL patients, the application of non-anthracycline-containing regimens have significantly improved the clinical outcome, contributing to higher response rate, longer overall survival and progression-free survival. Hematopoietic stem cell transplantation is widely recommended for consolidation after a complete remission or partial remission has been achieved. The anti-programmed death 1 antibody, an immune checkpoint inhibitor, has demonstrated favorable results in treating relapsed or refractory ENKL. Of the current ENKL treatment, researchers are still striving to validate how radiotherapy and chemotherapy should be optimally combined and which of the non-anthracycline-containing regimens is superior. In this review, we summarize the main genetic alterations frequently found in ENKL and their role in providing new insights into the therapeutic targets of this disease, and highlight the recent findings regarding new biologic markers, novel therapeutic strategies applied to this intriguing neoplasm.

Keywords: Epstein-Barr virus; diagnosis; extranodal natural killer/T-cell lymphoma; molecular pathogenesis; nasal type (ENKL); prognosis; treatment.

Figure 1

Molecular pathogenesis of Epstein-Barr virus-positive NK/T-cell lymphoma. EBV latent membrane protein-1 (LMP-1) activates the downstream signaling pathways, one of which is the NF-κB pathway. Together with PI3K/Akt pathways, NF-κB leads to the upregulation of survivin, which further inhibits cell apoptosis. Activation of JAK/STAT is associated with the upregulation of EZH2, which results in DNA methylation and gene transcription, and ultimately induces cell proliferation. Both the NF-κB pathway and JAK/STAT pathway upregulates the expression of PD-L1 on the surface of lymphoma cells and they escape from the immune surveillance of activated T cells. The deletion of chromosome 6q silences many tumor suppressor genes, such as PTPRK and PRDMI, which directly result in the activation of JAK/STAT and myc pathways. Moreover, gene mutation including P53, ECSIT, DDX3X are also involved in the oncogenesis of ENKL through the pathways mentioned above.

Figure 2

Promising new drugs or treatment strategies in NK/T cell lymphoma and their target. Pembrolizumab and nivolumab are both anti-PD1 antibodies, they were designed to target PD1 on the microenvironment T-cells, interrupting the connection of PD1 and PDL-1, and inhibiting activation. Daratumumab, a novel antibody targeting CD38 on the membrane of lymphoma cell, has shown particular efficacy in one case. LMP-specific CTLs are produced against lymphoma cells with membrane expression of LMP, and sequentially kill tumor cells. Signal pathways aberration and gene dysregulation are universally involved in lymphomagenesis, thus making molecule inhibitors an attractive target. JAK inhibitors, surviving, and EZH2 blocades have shown efficacy in some pre-clinical trials with favorable outcomes. The immunosuppressive agents, dexamethasone, and thalidomide, can efficaciously inhibit the TNF-α and IFN-γ released by lymphoma cells due to the ECSIT mutation, and relieve ENKL-associated hemophagocytic syndrome.