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.