Abstract
Epstein–Barr Virus (EBV) is present in neoplastic cells of 15% of Asian and Latin-American diffuse large B-cell lymphoma (DLBCL) patients. Even though a tolerogenic microenvironment was recently described in DLBCL, little is known concerning immunomodulatory features induced by EBV. As suggested in Hodgkin lymphoma, EBV-specific cytotoxic T-cells are increased but showing immune exhaustion features. Hence, host immunity suppression may play a critical role in tumor progression. This study aimed to investigate, whether an association between tumor microenvironment features and EBV presence is taking place, and its clinical correlate. The incidence of EBV+DLBCL NOS was 12.6% in this cohort. Cytokine and chemokine transcripts expression and immunophenotype analysis showed that EBV infection was associated with increased gene expression of immunosuppressive cytokine (IL-10) together with increased CD8+ T-cells and granzyme B+ cytotoxic effector cells. However, this specific response coexists with a tolerogenic milieu, by PD-1 expression, in EBV+ and EBV−DLBCL cases. High PD-1+ cell counts, EBV presence and low CCL22 expression were associated with worse survival, supporting our hypothesis that EBV-specific response is mounted locally and its inhibition by, for example PD-1+ cells, may negatively affect outcome. The better understanding of the interplay between lymphoma cells and microenvironment in a viral framework could thereby facilitate the discovery of new targets for innovative anti-lymphoma treatment strategies.
Highlights
In the last few years, the role of Epstein–Barr Virus (EBV) in the pathogenesis of diffuse large B cell lymphoma (DLBCL) has become an awkward issue
PD-1 is expressed by tumor-infiltrating lymphocytes (TILs) in the microenvironment in several hematologic malignancies including follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and Hodgkin lymphoma (HL)[23,24,25]
In this analysis we presented the results of a whole DLBCL cohort from the combination of two reported series, comprising a wide age-range of patients (2–84 years)
Summary
In the last few years, the role of EBV in the pathogenesis of diffuse large B cell lymphoma (DLBCL) has become an awkward issue. Since 2008, World Health Organization (WHO) classification of lymphoid malignancies includes a new provisional entity, EBV-positive DLBCL of the elderly[2] This DLBCL subtype is defined in people older than 50 years without any known immunodeficiency, characterized by advanced clinical stage and latent EBV infection[3]. Persistent antigenic stimulation (e.g., chronic infections), leads to CD8+ T-cell exhaustion, characterized by the induction of a hypoproliferative state and the subsequent loss of the ability to produce antiviral cytokines[21] As a result, this T-cell exhaustion plays an important role in the development of cancer including hematologic malignancies[22]. We investigated the association between tumor EBV infection, clinical features and the expression of a number of cell markers, cytokines and chemokines within the tumor microenvironment of a cohort of patients with DLBCL from Latin America using molecular techniques and immunohistochemistry methods, to shed light on some aspects of the relationship between infection, tumor and host immunity
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