High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients

Regulatory T cells (T(reg)) inhibit the generation of host-versus-tumor immunity via suppression of tumor-specific effector T-cell responses and development of immune tolerance to neoplastic cells. The transcription factor forkhead box P3 (FOXP3) is an intracellular key molecule for T(reg) development and function and is considered to represent the most specific T(reg) cell marker. The aim of this study was to analyze the frequency and prognostic impact of tumor-infiltrating FOXP3(+) T(reg) in colorectal cancer (CRC) stratified by mismatch-repair (MMR) status. Using the tissue microarray technique, 1,420 tumor samples were immunohistochemically stained for FOXP3 and stratified into 1,197 MMR-proficient and 223 MMR-deficient CRCs. Additionally, the 1,197 MMR-proficient CRCs were randomized into 2 subgroups (Test Groups 1 and 2; n = 613 and 584, respectively). In both MMR-proficient CRC subgroups high frequency tumor-infiltrating FOXP3(+) T(reg) was associated with early T stage (p = 0.001 and <0.001), tumor location (p = 0.01 and 0.045) and increased 5-year survival rate (p = 0.004 and <0.001), whereas in MMR-deficient CRCs an association between FOXP3(+) T(reg) and absence of lymph node involvement (p = 0.023), absence of vascular invasion (p = 0.023) and improved 5-year survival rate (p = 0.029) could be detected. In a multivariable analysis including age, gender, T stage, N stage, tumor grade, vascular invasion, and tumor border configuration, a high FOXP3(+) T(reg) frequency was an independent prognostic factor in both MMR-proficient CRC subsets (p = 0.019 and p = 0.007), but not in the MMR-deficient CRCs (p = 0.13). Therefore, high frequency of tumor-infiltrating FOXP3(+) T(reg) is associated with early T stage and independently predicts improved disease-specific survival in MMR-proficient CRC patients.