Epstein–Barr virus infection induces an increase of T regulatory type 1 cells in Hodgkin lymphoma patients

Moralès, Olivier; Mrizak, Dhafer; François, Violaine; Mustapha, Rami; Miroux, Céline; Depil, Stéphane; Decouvelaere, Anne‐Valérie; Lionne‐Huyghe, Pauline; Auriault, C.; Launoit, Yvan de; Pancré, Véronique; Delhem, Nadira

doi:10.1111/bjh.12980

Cited by 51 publications

(52 citation statements)

References 51 publications

(65 reference statements)

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“…We hypothesize that these are regulatory type 1 (Tr1) cells, a Foxp3 - , IL-10 producing subtype of inducible Treg cells. Tr1 cells are not as well characterized as Foxp3 + Treg cells and have not received the same focus in tumor immunology research, but previous studies suggested that EBV, including other EBV + tumors, induces Tr1 cells [7, 32]. The presence of Tr1 cells could indicate that Foxp3 + Treg cells are not the only cell type restricting eBL tumor response, which has implications for future Treg-modulating therapy in eBL.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T Cells in Endemic Burkitt Lymphoma Patients Are Associated with Poor Outcomes: A Prospective, Longitudinal Study

et al. 2016

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Deficiencies in Epstein-Barr virus (EBV)-specific T cell immunosurveillance appear to precede the development of endemic Burkitt lymphoma (eBL), a malaria-associated pediatric cancer common in sub-Saharan Africa. However, T cell contributions to eBL disease progression and survival have not been characterized. Our objective was to investigate regulatory and inflammatory T cell responses in eBL patients associated with clinical outcomes. By multi-parameter flow cytometry, we examined peripheral blood mononuclear cells from 38 eBL patients enrolled in a prospective cohort study in Kisumu, Kenya from 2008–2010, and 14 healthy age-matched Kenyan controls. Children diagnosed with eBL were prospectively followed and outcomes categorized as 2-year event-free survivors, cases of relapses, or those who died. At the time of diagnosis, eBL children with higher CD25+Foxp3+ regulatory T (Treg) cell frequencies were less likely to survive than patients with lower Treg frequencies (p = 0·0194). Non-survivors also had higher absolute counts of CD45RA+Foxp3lo naïve and CD45RA-Foxp3hi effector Treg subsets compared to survivors and healthy controls. Once patients went into clinical remission, Treg frequencies remained low in event-free survivors. Patients who relapsed, however, showed elevated Treg frequencies months prior to their adverse event. Neither concurrent peripheral blood EBV load nor malaria infection could explain higher Treg cell frequencies. CD8+ T cell PD-1 expression was elevated in all eBL patients at time of diagnosis, but relapse patients tended to have persistently high PD-1 expression compared to long-term survivors. Non-survivors produced more CD4+ T-cell IL-10 in response to both Epstein-Barr Nuclear Antigen-1 (EBNA-1) (p = 0·026) and the malaria antigen Plasmodium falciparum Schizont Egress Antigen-1 (p = 0·0158) compared to survivors, and were concurrently deficient in (EBNA-1)-specific CD8+ T-cell derived IFN-γ production (p = 0·002). In addition, we identified the presence of Foxp3-IL10+ regulatory Type 1 cells responding to EBNA-1 in contrast to the malaria antigen tested. These novel findings suggest that poor outcomes in eBL patients are associated with a predominantly immuno-regulatory environment. Therefore, Treg frequencies could be a predictive biomarker of disease progression and manipulation of Treg activity has potential as a therapeutic target to improve eBL survival.

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Section: Discussionmentioning

confidence: 99%

Regulatory T Cells in Endemic Burkitt Lymphoma Patients Are Associated with Poor Outcomes: A Prospective, Longitudinal Study

et al. 2016

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“…Many reports do not differentiate between EBVpositive and EBV-negative cases, but this distinction is important to make because, although the two subtypes appear superficially similar, several important differences exist between them, namely the tumour immune microenvironment. Firstly, EBV-positive HL has a distinct gene signature with markers indicating cytotoxic and Th1 responses being increased (Chetaille et al 2009;Barros et al 2012) although markers of suppression such as LAG-3 and IL-10 are also raised (Morales et al 2014). Secondly, while the frequency of regulatory T cells is increased in the blood and particularly the tumour infiltrates of HL patients (Marshall et al 2004), the presence of EBV correlates with higher numbers of both natural and induced regulatory T cells (Assis et al 2012;Morales et al 2014).…”

Section: Suppression Of Ebv-specific T-cell Responses In Patients Witmentioning

confidence: 99%

“…Firstly, EBV-positive HL has a distinct gene signature with markers indicating cytotoxic and Th1 responses being increased (Chetaille et al 2009;Barros et al 2012) although markers of suppression such as LAG-3 and IL-10 are also raised (Morales et al 2014). Secondly, while the frequency of regulatory T cells is increased in the blood and particularly the tumour infiltrates of HL patients (Marshall et al 2004), the presence of EBV correlates with higher numbers of both natural and induced regulatory T cells (Assis et al 2012;Morales et al 2014). The increased numbers of the former in EBV-positive disease may stem from EBNA1-mediated upregulation of CCL20 in the malignant Hodgkin/ReedSternberg cells (Baumforth et al 2008).…”

Section: Suppression Of Ebv-specific T-cell Responses In Patients Witmentioning

confidence: 99%

T-Cell Responses to EBV

Hislop

Taylor

2015

Epstein Barr Virus Volume 2

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Epstein-Barr virus (EBV) is arguably one of the most successful pathogens of humans, persistently infecting over ninety percent of the world's population. Despite this high frequency of carriage, the virus causes apparently few adverse effects in the vast majority of infected individuals. Nevertheless, the potent growth transforming ability of EBV means the virus has the potential to cause malignancies in infected individuals. Indeed, EBV is thought to cause 1% of human malignancies, equating to 200,000 malignancies each year. A clear factor as to why virus-induced disease is relatively infrequent in healthy infected individuals is the presence of a potent immune response to EBV, in particular, that mediated by T cells. Thus, patient groups with immunodeficiencies or whose cellular immune response is suppressed have much higher frequencies of EBV-induced disease and, in at least some cases, these diseases can be controlled by restoration of the T-cell compartment. In this chapter, we will primarily review the role the αβ subset of T cells in the control of EBV in healthy and diseased individuals.

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“…The major clinical experience with EBV-CTLs has been in EBV-associated post-transplant lymphoproliferative disease (PTLD) and HL (105-107). In recent years, EBV-CTLs therapy has also been applied to ENKL as consolidation post chemo-radiotherapy or in the relapsed/refractory setting (108).…”

Section: Immunotherapeutic Strategies For T Cell Leukemia and Lymphomamentioning

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 infection induces an increase of T regulatory type 1 cells in Hodgkin lymphoma patients

Cited by 51 publications

References 51 publications

Regulatory T Cells in Endemic Burkitt Lymphoma Patients Are Associated with Poor Outcomes: A Prospective, Longitudinal Study

Regulatory T Cells in Endemic Burkitt Lymphoma Patients Are Associated with Poor Outcomes: A Prospective, Longitudinal Study

T-Cell Responses to EBV

Novel Immunotherapies for T Cell Lymphoma and Leukemia

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