Tumor-Infiltrating FOXP3+ T Regulatory Cells Show Strong Prognostic Significance in Colorectal Cancer

Abstract

Purpose: To determine the prognostic significance of FOXP3⁺ lymphocyte (Treg) density in colorectal cancer compared with conventional histopathologic features and with CD8⁺ and CD45RO⁺ lymphocyte densities. Patients and Methods: Tissue microarrays and immunohistochemistry were used to assess the densities of CD8⁺, CD45RO⁺, and FOXP3⁺ lymphocytes in tumor tissue and normal colonic mucosa from 967 stage II and stage III colorectal cancers. These were evaluated for associations with histopathologic features and patient survival. Results: FOXP3⁺ Treg density was higher in tumor tissue compared with normal colonic mucosa, whereas CD8⁺ and CD45RO⁺ cell densities were lower. FOXP3⁺ Tregs were not associated with any histopathologic features, with the exception of tumor stage. Multivariate analysis showed that stage, vascular invasion, and FOXP3⁺ Treg density in normal and tumor tissue were independent prognostic indicators, but not CD8⁺ and CD45RO⁺. High FOXP3⁺ Treg density in normal mucosa was associated with worse prognosis (hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.13; P = .019). In contrast, a high density of FOXP3⁺ Tregs in tumor tissue was associated with improved survival (HR = 0.54; 95% CI, 0.38 to 0.77; P = .001). Conclusion: FOXP3⁺ Treg density in normal and tumor tissue had stronger prognostic significance in colorectal cancer compared with CD8⁺ and CD45RO⁺ lymphocytes. The finding of improved survival associated with a high density of tumor-infiltrating FOXP3⁺ Tregs in colorectal cancer contrasts with several other solid cancer types. The inclusion of FOXP3⁺ Treg density may help to improve the prognostication of early-stage colorectal cancer.