Epstein–Barr virus-associated lymphomas

Shannon-Lowe, Claire; Rickinson, Alan B.; Bell, Andrew I.

doi:10.1098/rstb.2016.0271

Cited by 344 publications

(357 citation statements)

References 148 publications

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“…12,13 It is postulated that all these factors contribute to a tolerogenic environment that promotes tumour immune escape, 14 much as iatrogenic immunosuppression does in EBV -pos post-transplant lymphoproliferative disorders. [15][16][17][18] Interestingly, we have previously shown that the T-cell receptor repertoire is a key determinant of the TME and is associated with outcome. 19 Furthermore, substantially higher clonal T-cell responses were observed in EBV -pos vs EBV -neg DLBCL.…”

Section: Introductionmentioning

confidence: 99%

The tumour microenvironment is immuno‐tolerogenic and a principal determinant of patient outcome in EBV‐positive diffuse large B‐cell lymphoma

Keane

Tobin

Gunawardana

et al. 2019

European J of Haematology

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ObjectiveEpstein‐Barr virus‐positive diffuse large B‐cell lymphoma (EBV‐pos DLBCL) is a recently identified entity. Data regarding outcome to frontline immuno‐chemotherapy are conflicting. Although the prognostic impact of the tumour microenvironment (TME) in EBV‐neg DLBCL is well‐established, it remains untested whether the TME influences survival in EBV‐pos DLBCL. There are no data with new digital gene expression technologies that simultaneously interrogate the virus, B cells and the tumour microenvironment (TME).MethodsWe used the NanoString™ platform in a population‐based cohort of 433 patients to establish if the technology could detect EBV in the tumour biopsies and to investigate the influence that EBV has on the complex tumour microenvironment of DLBCL.ResultsIncidence of EBV‐pos DLBCL was 6.9% with 5‐year survival of 65% vs 82% in EBV‐neg DLBCL (P = 0.018). EBV‐pos tissues had similar expression of T‐cell genes compared to EBV‐neg DLBCL but higher levels of the antigen‐presenting molecule B2M. This was countered by elevated PD‐L1, PD‐L2, LAG3 and TIM3 immune checkpoints and a higher CD163/CD68 “M2” macrophage score.ConclusionIn EBV‐pos DLBCL, the TME is immuno‐tolerogenic and may explain the poor outcomes seen in this subtype of DLBCL.

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Section: Introductionmentioning

confidence: 99%

The tumour microenvironment is immuno‐tolerogenic and a principal determinant of patient outcome in EBV‐positive diffuse large B‐cell lymphoma

Keane

Tobin

Gunawardana

et al. 2019

European J of Haematology

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“…In ENKL, one of the main oncogenic driver, NF-kB, is driven by the EBV protein LMP1. LMP1 and NF-kB activate a series of genes that lead to the production of Th1 cytokines TNF-α and IFN-γ(34, 41). Moreover, in ENKL EBV infection promotes the upregulation on infected lymphoma cells of the PD-L1.…”

Section: Immune System In T Cell Neoplasms – Rationale For Immunotherapymentioning

confidence: 99%

“…Moreover, in ENKL EBV infection promotes the upregulation on infected lymphoma cells of the PD-L1. Binding of PD-L1 on lymphoma cells by PD1 on effector T cells suppresses T cell toxicity, allowing ENKL to escape this regulation(34, 41). This might explain the good activity of checkpoint inhibitors in ENKL.…”

Section: Immune System In T Cell Neoplasms – Rationale For Immunotherapymentioning

confidence: 99%

Novel Immunotherapies for T Cell Lymphoma and Leukemia

Ghione

Moskowitz

Paola

et al. 2018

Curr Hematol Malig Rep

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Purpose of review: novel immunotherapies such as checkpoint inhibitors, bispecific and chimeric antigen receptor T cells are leading to promising responses when treating solid tumors and hematological malignancies. T cell neoplasms include leukemia and lymphomas that are derived from T cells. These are rare diseases with generally poor clinical outcomes. This review describes the rational and preliminary results of these approaches for people with T cell lymphoma and leukemia. Recent findings: for T cell neoplasms, despite significant research effort, only few agents, such as monoclonal antibodies and allogeneic stem cell transplantation, showed some clinical activity. One of the major hurdles to targeting T cell neoplasms is that activation or elimination of T cells, either normal or neoplastic, can cause significant toxicity. A need to develop novel safe and effective immunotherapies for T cell neoplasms exists. Summary: In this review, we will discuss the rationale for immunotherapy of T cell leukemia and lymphoma and present the most recent therapeutic approaches.

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“…Epstein-Barr virus (EBV) infects nearly 95% of adults worldwide. The virus primarily causes infectious mononucleosis (IM) in adolescents, is closely associated with lymphoproliferative disease in immunocompromised individuals, and is linked to cancers including Burkitt lymphomas (BL), diffuse large B cell lymphomas (DLBCL), and nasopharyngeal carcinoma (1, 2). BL is a common childhood cancer in Africa, and >80% of cases are EBV positive (3).…”

Section: Introductionmentioning

confidence: 99%

“…BL is a common childhood cancer in Africa, and >80% of cases are EBV positive (3). As a germinal-center (GC) derived cancer, BL cells exhibit a centroblast-like phenotype (2, 4), maintained in part from activated c-myc oncogene expression (5), and have a molecular profile akin to GC dark zone proliferative B cells (6).…”

Section: Introductionmentioning

confidence: 99%

B Cell Receptor-Responsive miR-141 and viral miR-BART9 promote Epstein-Barr Virus Reactivation Through FOXO3 Inhibition

Chen

Fachko

Ivanov

et al. 2019

Preprint

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6Antigen recognition by the B cell receptor (BCR) is a physiological trigger for reactivation of Epstein-Barr virus 7(EBV) and can be recapitulated in vitro by cross-linking of surface immunoglobulins. Previously, we identified a 8 subset of EBV microRNAs (miRNAs) that attenuate BCR signal transduction and subsequently, dampen lytic 9replication in B cells. The roles of host miRNAs in virus reactivation are not completely understood. To 10 investigate this process, we profiled the small RNAs in latently infected and reactivated Burkitt's lymphoma 11 cells, and identified several miRNAs, such as miR-141, that are induced upon BCR cross-linking. Notably, EBV 12 encodes a viral miRNA, miR-BART9, with sequence homology to miR-141. To better understand the functions 13 of these two miRNAs, we examined their molecular targets and experimentally validated multiple candidates 14 commonly regulated by both miRNAs. Targets included transcriptional regulators of the EBV immediate early 15promoters and B cell transcription factors, leading us to hypothesize that these miRNAs modulate kinetics of 16 the latent to lytic switch in B cells. Through functional assays, we identified roles for miR-141 and EBV miR-17 BART9 and one specific target, FOXO3, in lytic reactivation. Our data support a model whereby EBV exploits 18BCR-responsive miR-141 and further mimics activity of this miRNA family via a viral miRNA to promote 19 productive virus replication. 20 Importance 21EBV is a human pathogen associated with several malignancies. A key aspect of lifelong virus persistence is 22 the ability to switch between latent and lytic replication modes. Mechanisms governing latency and lytic 23 reactivation are only partly understood, and how the EBV latent to lytic switch is post-transcriptionally regulated 24remains an outstanding question. This study sheds light on how miR-141 expression is regulated in Burkitt's 25 lymphoma cells, and identifies a role for FOXO3, a common target of both miR-141 and viral miR-BART9, in 26 modulating EBV reactivation. 27 28

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Epstein–Barr virus-associated lymphomas

Cited by 344 publications

References 148 publications

The tumour microenvironment is immuno‐tolerogenic and a principal determinant of patient outcome in EBV‐positive diffuse large B‐cell lymphoma

The tumour microenvironment is immuno‐tolerogenic and a principal determinant of patient outcome in EBV‐positive diffuse large B‐cell lymphoma

Novel Immunotherapies for T Cell Lymphoma and Leukemia

B Cell Receptor-Responsive miR-141 and viral miR-BART9 promote Epstein-Barr Virus Reactivation Through FOXO3 Inhibition

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