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

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.