Epstein-Barr virus infection and clinical outcome in breast cancer patients correlate with immune cell TNF-α/IFN-γ response

BMC Cancer

Emmanuel Drouet¹  Carlos Freire de Oliveira⁴  Patrice Morand³  Teresa Simões da Silva⁷  Samira Fafi-Kremer⁵  Sofia Franco⁴  Catherine Fallecker¹  Dominique Bicout⁶  Artur Paiva²  Mohammed Habib¹  Gina Marrão² 

[1]Université de Grenoble-Alpes, Unit for Virus Host-Cell Interactions, UMI 3265 UJF-CNRS-EMBL, CIBB, 71 Avenue des Martyrs, F-38042 Grenoble, Cedex 9, France

[2]Portuguese Institute for Blood and Transplantation, University Hospital, Coimbra, Portugal

[3]Unit of Virology, University Hospital, Grenoble, France

[4]Department of Gynecology, University Hospital, Coimbra, & Faculty of Medicine, University of Coimbra, Coimbra, Portugal

[5]Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, Strasbourg, France

[6]Team Environment and Health Prediction in Populations Unit – TIMC Laboratory, UMR CNRS 5525, Université Joseph Fourier, Grenoble, France

[7]Department of Pathology, University Hospital, Coimbra, Portugal

关键词: ZEBRA;    Multivariate analysis;    Survival;    TNF-α;    IFN-γ;    Immunocompetent cells;    Tumor;    Viral load;    EBV;    Breast cancer;   

Others  :  1121089
DOI  :  10.1186/1471-2407-14-665

 received in 2014-03-13, accepted in 2014-09-08,  发布年份 2014

【 摘 要 】

Background

For nearly two decades now, various studies have reported detecting the Epstein-Barr virus (EBV) in breast cancer (BC) cases. Yet the results are unconvincing, and their interpretation has remained a matter of debate. We have now presented prospective data on the effect of EBV infection combined with survival in patients enrolled in a prospective study.

Methods

We assessed 85 BC patients over an 87-month follow-up period to determine whether EBV infection, evaluated by qPCR in both peripheral blood mononuclear cells (PBMCs) and tumor biopsies, interacted with host cell components that modulate the evolution parameters of BC. We also examined the EBV replicating form by the titration of serum anti-ZEBRA antibodies. Immunological studies were performed on a series of 35 patients randomly selected from the second half of the survey, involving IFN-γ and TNF-α intracellular immunostaining tests performed via flow cytometry analysis in peripheral NK and T cells, in parallel with EBV signature. The effect of the EBV load in the blood or tumor tissue on patient survival was analyzed using univariate and multivariate analyses, combined with an analysis of covariance.

Results

Our study represents the first ever report of the impact of EBV on the clinical outcome of BC patients, regardless of tumor histology or treatment regimen. No correlation was found between: (i) EBV detection in tumor or PBMCs and tumor characteristics; (ii) EBV and other prognostic factors. Notably, patients exhibiting anti-ZEBRA antibodies at high titers experienced poorer overall survival (p = 0.002). Those who recovered from their disease were found to have a measurable EBV DNA load, together with a high frequency of IFN-γ and TNF-α producing PBMCs (p = 0.04), which indicates the existence of a Th1-type polarized immune response in both the tumor and its surrounding tissue.

Conclusions

The replicative form of EBV, as investigated using anti-ZEBRA titers, correlated with poorer outcomes, whereas the latent form of the virus that was measured and quantified using the EBV tumor DNA conferred a survival advantage to BC patients, which could occur through the activation of non-specific anti-tumoral immune responses.

【 授权许可】

   
2014 Marrão et al.; licensee BioMed Central Ltd.

【 图 表 】

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