High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma

Abstract

The tumor microenvironment plays an important role in the biologic behavior of follicular lymphoma (FL), but the specific cell subsets involved in this regulation are unknown. To determine the impact of FOXP3-positive regulatory T cells (Tregs) in the progression and outcome of FL patients, we examined samples from 97 patients at diagnosis and 37 at first relapse with an anti-FOXP3 monoclonal antibody. Tregs were quantified using computerized image analysis. The median overall survival (OS) of the series was 9.9 years, and the FL International Prognostic Index (FLIPI) was prognostically significant. The median Treg percentage at diagnosis was 10.5%. Overall, 49 patients had more than 10% Tregs, 30 between 5% to 10%, and 19 less than 5%, with a 5-year OS of 80%, 74%, and 50%, respectively (P ‫؍‬ .001). Patients with very low numbers of Tregs (< 5%) presented more frequently with refractory disease (P ‫؍‬ .007). The prognostic significance of Treg numbers was independent of the FLIPI. Seven transformed diffuse large B-cell lymphomas (DLBCLs) had lower Treg percentages (mean: 3.3%) than FL grades 1,2 (mean: 12.1%) or 3 (mean: 9%) (P < .02).

Cancer-Immune Equilibrium: Questions Unanswered

“…However, data also suggest an increase in numbers of intratumoral Treg is not always associated with poor prognosis but may in fact correlate with good prognosis. Such findings have been reported for follicular lymphoma and Hodgkin's lymphoma [65,66]. Whether the above findings, applicable to cancer in general can be extended to equilibrium phase as well or not remains to be investigated.…”

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

“…Such a good prognostic value of Tregs in head and neck cancer has subsequently been confirmed by others [98,99] and extended to additional solid neoplasms including colorectal carcinoma [100,101] and bladder cancer [102]. In some tumor types including hepatocellular carcinoma and breast cancer, high levels of intratumoral Tregs have been clearly associated with bad prognosis, whereas in other types such as colorectal cancer, head and neck carcinoma and lymphoma, robust tumor infiltration by Tregs frequently correlates with improved disease outcome [103,104].…”

An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer

“…In agreement with this hypothesis, higher numbers of tumour-infiltrating T reg were shown to be associated with poor outcome in pancreatic [25] and hepatocellular [27] carcinomas. In follicular lymphoma, head and neck, and ovarian cancer the number of infiltrating FOXP3 + immune cells has shown to be an independent prognostic factor [47][48][49]. However, studies of other tumours have led to conflicting results.…”