Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma

Background The tumor microenvironment is important for the behavior of cancer. We assessed the distribution and biological significance of FOXP3+ regulatory T-cells (Treg) in lymphomas. Design and Methods The absolute number of intratumoral FOXP3+ cells was immunohistochemically studied on lymphoma tissue microarrays from 1019 cases of different types of lymphomas and correlated to phenotypic and clinical parameters in uni- and multivariate models. Receiver operating characteristic -curves were used to determine prognostic cut-off values of FOXP3+ cell density. Results Of the 1019 cases, 926 (91%) were evaluable. FOXP3+ cell density varied between the lymphoma entities, and was highest in follicular lymphoma. An increased number of tumor-infiltrating FOXP3+ cells over the receiver operating characteristic-determined cut-offs positively influenced both disease-specific and failure-free survival in follicular lymphoma ( p =0.053) and disease-specific survival in germinal center-like diffuse large B-cell lymphoma ( p =0.051) and overall and failure-free survival in classical Hodgkin’s lymphoma ( p =0.004), but had a negative prognostic effect in non-germinal center diffuse large B-cell lymphoma ( p =0.059). In a Cox regression model, considering stage and age, the amount of FOXP3+ cells was of independent prognostic significance for failure-free survival in classical Hodgkin’s lymphoma and of borderline significance for overall survival in classical Hodgkin’s lymphoma and disease-specific survival in germinal center-like and non-germinal center diffuse large B-cell lymphoma. Conclusions FOXP3+ cells represent important lymphoma/host microenvironment modulators. Assessment of FOXP3+ cell density can contribute to the prediction of outcome in diffuse large B-cell lymphoma, fallicular lymphoma and classical Hodgkin’s lymphoma.