Epstein–Barr virus-specific CD8+ T lymphocytes from diffuse large B cell lymphoma patients are functionally impaired

Cárdenas, Denny Miley; Vélez, Gabriel; Órfão, Alberto; Herrera, María Victoria; Solano, Julio; Olaya, Mercedes; Uribe, Ana Fernanda; Saavedra, Carlos; Duarte, Mónica; Rodríguez, Marisa; López, Marcos; Fiorentino, Susana; Quijano, Sandra

doi:10.1111/cei.12682

Cited by 21 publications

(31 citation statements)

References 61 publications

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“…Notably, CTLA4 mutation carrier NK cells show defective effector functions, but normal peripheral maturation ( 28 ). Furthermore, EBV-specific CD8+ T cells in EBV-associated DLBCL ( CTLA4 wildtype) are functionally impaired, hence, CTLA-4 insufficiency might push the oncogenic capacity of EBV ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers

et al. 2018

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Background: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative immune regulator on the surface of T cells. In humans, heterozygous germline mutations in CTLA4 can cause an immune dysregulation syndrome. The phenotype comprises a broad spectrum of autoinflammatory, autoimmune, and immunodeficient features. An increased frequency of malignancies in primary immunodeficiencies is known, but their incidence in CTLA-4 insufficiency is unknown.Methods: Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 CTLA4 mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled.Results: Among the 184 CTLA4 mutation carriers, 131 were considered affected, indicating a penetrance of 71.2%. We documented 17 malignancies, which amounts to a cancer prevalence of 12.9% in affected CTLA4 mutation carriers. There were ten lymphomas, five gastric cancers, one multiple myeloma, and one metastatic melanoma. Seven lymphomas and three gastric cancers were EBV-associated.Conclusion: Our findings demonstrate an elevated cancer risk for patients with CTLA-4 insufficiency. As more than half of the cancers were EBV-associated, the failure to control oncogenic viruses seems to be part of the CTLA-4-insufficient phenotype. Hence, lymphoproliferation and EBV viral load in blood should be carefully monitored, especially when immunosuppressing affected CTLA4 mutation carriers.

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Section: Discussionmentioning

confidence: 99%

Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers

et al. 2018

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“…On the other hand, a regulatory profile characterized both EBV+ and EBV− HL microenvironment 43 , which coexists with the immune effector cells. Previous reports have suggested that, in patients who develop lymphomas, EBV-specific subsets of circulating T cells are dysfunctional for IFN-γ secretion 44 , showing signs of immune exhaustion in association with increased soluble IL-10 levels 35 . Therefore, in our DLBCL series, cytotoxicity assessed by CD8+ cells and GrB+ expression could not be effective due to immune exhaustion, contributing to the pathogenesis of DLBCL.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic response against Epstein Barr virus coexists with diffuse large B-cell lymphoma tolerogenic microenvironment: clinical features and survival impact

Cohen

Vistarop

Huaman³

et al. 2017

Sci Rep

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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.

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“…The classical EBV+ DLBCL observed in the elderly is thought to arise as a consequence of an age-related senescence of EBV-specific T cell surveillance. The precise nature of the senescence-associated defects in T cell immunity have not yet been well defined, although a narrowing of the EBV-specific TCR-Vβ repertoire with reduced EBV-specific effector memory CD4 + and CD8 + T cell numbers has been described [ 86 ]. Consistent with reduced T cell immunity, these tumours usually display a Latency III viral gene expression profile [ 87 ], similar to that seen in the B-LPD lesions arising in immunosuppressed transplant recipients or in late-stage AIDS.…”

Section: Diffuse Large B Cell Lymphomamentioning

confidence: 99%

Epstein–Barr virus-associated lymphomas

Shannon-Lowe

Rickinson

Bell

2017

Phil. Trans. R. Soc. B

342

305

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Epstein–Barr virus (EBV), originally discovered through its association with Burkitt lymphoma, is now aetiologically linked to a remarkably wide range of lymphoproliferative lesions and malignant lymphomas of B-, T- and NK-cell origin. Some occur as rare accidents of virus persistence in the B lymphoid system, while others arise as a result of viral entry into unnatural target cells. The early finding that EBV is a potent B-cell growth transforming agent hinted at a simple oncogenic mechanism by which this virus could promote lymphomagenesis. In reality, the pathogenesis of EBV-associated lymphomas involves a complex interplay between different patterns of viral gene expression and cellular genetic changes. Here we review recent developments in our understanding of EBV-associated lymphomagenesis in both the immunocompetent and immunocompromised host.This article is part of the themed issue ‘Human oncogenic viruses’.

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Epstein–Barr virus-specific CD8+ T lymphocytes from diffuse large B cell lymphoma patients are functionally impaired

Cited by 21 publications

References 61 publications

Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers

Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers

Cytotoxic response against Epstein Barr virus coexists with diffuse large B-cell lymphoma tolerogenic microenvironment: clinical features and survival impact

Epstein–Barr virus-associated lymphomas

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