Increased expression of CD4+CD25+FOXP3+ regulatory T cells correlates with Epstein–Barr virus and has no impact on survival in patients with classical Hodgkin lymphoma in Brazil

Assis, Mariane Cristina Gennari; Campos, Antônio Hugo José Fróes Marques; Oliveira, José Salvador Rodrigues de; Soares, Fernando Augusto; Silva, Joyce M. K.; Silva, Priscilla B.; Penna, Adriana D.; Souza, Eni M.; Baiocchi, Otavio C. G.

doi:10.1007/s12032-012-0299-4

Cited by 36 publications

(31 citation statements)

References 17 publications

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“…In previous studies, when subjects were included from all age groups, FOXP3 + regulatory T cells (Tregs) dominated the TME of EBV-positive CHL, as shown in the current study. [13][14][15] However, in pediatric patients younger than 10 years, there was no difference in the proportion of Tregs between EBV-positive and -negative cases, while GrB + CTL was increased in EBV-positive CHL. 16 These studies indicate the importance of age in the involvement of EBV in CHL.…”

Section: Discussionmentioning

confidence: 97%

Tumor Microenvironment and RIG-I Signaling Molecules in Epstein Barr Virus-Positive and -Negative Classical Hodgkin Lymphoma of the Elderly

Satoh

Wada

Yajima

et al. 2014

J Clin Exp Hematopathol

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Classical Hodgkin lymphoma (CHL) is a B-cell neoplasm characterized by Hodgkin and Reed-Sternberg (HRS) cells. Its prevalence exhibits a bimodal pattern of peaking in young adults and the elderly. There is an association with Epstein-Barr virus (EBV) infection in about 50% of cases of CHL of the elderly, and the outcome of these patients is unfavorable. It is not well known how the latent infection of EBV is involved in the pathophysiology of CHL of the elderly. To address this issue, we examined the tumor microenvironment (TME) and the expression of molecules related to EBV infection in HRS cells in 10 EBV-positive CHL and 7 EBV-negative CHL patients older than 50 years. In EBV-positive CHL, we found an increased population of FOXP3(+) cells, while that of granzyme B(+) cells was reduced, compared with those in EBV-negative CHL. The expression of inhibitory chemokine CCL20 was increased in EBV-positive HRS cells compared with that in EBV-negative HRS cells. In addition, despite increased expression of a pattern recognition receptor, RIG-I, in intracellular innate immunity, there was no evidence of interferon regulatory factor 3 activation or interferon-ß induction in EBV-positive HRS cells in CHL of the elderly. The disease recurred frequently (50%) in EBV-positive CHL. The current study thus suggests the possibility that the latent infection of EBV alters the expression of chemokines and the innate immunity response in HRS cells and modulates TME to an immunosuppressive state, which may account for the unfavorable disease course in CHL of the elderly.

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Section: Discussionmentioning

confidence: 97%

Tumor Microenvironment and RIG-I Signaling Molecules in Epstein Barr Virus-Positive and -Negative Classical Hodgkin Lymphoma of the Elderly

Satoh

Wada

Yajima

et al. 2014

J Clin Exp Hematopathol

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“…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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“…However, not all reports have found a correlation between high Treg levels and poor outcomes [16–18]. The goal of this study was to investigate the regulatory T cell populations and their predictive value for disease outcome in children diagnosed with eBL.…”

Section: Introductionmentioning

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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Increased expression of CD4+CD25+FOXP3+ regulatory T cells correlates with Epstein–Barr virus and has no impact on survival in patients with classical Hodgkin lymphoma in Brazil

Cited by 36 publications

References 17 publications

Tumor Microenvironment and RIG-I Signaling Molecules in Epstein Barr Virus-Positive and -Negative Classical Hodgkin Lymphoma of the Elderly

Tumor Microenvironment and RIG-I Signaling Molecules in Epstein Barr Virus-Positive and -Negative Classical Hodgkin Lymphoma of the Elderly

T-Cell Responses to EBV

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

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