Department of Surgery, University Hospital of Basel, Basel, Switzerland.
Int J Cancer. 2010 Jun 1;126(11):2635-43. doi: 10.1002/ijc.24989.
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.
调节性 T 细胞（Treg）通过抑制肿瘤特异性效应 T 细胞反应和对肿瘤细胞产生免疫耐受来抑制宿主抗肿瘤免疫。叉头框 P3（FOXP3）转录因子是 Treg 发育和功能的关键细胞内分子，被认为是最特异的 Treg 细胞标志物。本研究旨在分析结直肠癌（CRC）中肿瘤浸润性 FOXP3+Treg 的频率及其与错配修复（MMR）状态的相关性。本研究采用组织微阵列技术，对 1420 例肿瘤样本进行 FOXP3 免疫组化染色，并根据 MMR 状态分为 1197 例 MMR 有效的 CRC 和 223 例 MMR 缺失的 CRC。此外，将 1197 例 MMR 有效的 CRC 随机分为 2 个亚组（测试组 1 和 2；n=613 和 584）。在 MMR 有效的 CRC 亚组中，高频率的肿瘤浸润性 FOXP3+Treg 与早期 T 分期（p=0.001 和 <0.001）、肿瘤位置（p=0.01 和 0.045）和增加的 5 年生存率（p=0.004 和 <0.001）相关，而在 MMR 缺失的 CRC 中，FOXP3+Treg 与无淋巴结受累（p=0.023）、无血管侵犯（p=0.023）和改善的 5 年生存率（p=0.029）相关。在包括年龄、性别、T 分期、N 分期、肿瘤分级、血管侵犯和肿瘤边界形态在内的多变量分析中，高 FOXP3+Treg 频率是 MMR 有效的 CRC 亚组中独立的预后因素（p=0.019 和 p=0.007），但在 MMR 缺失的 CRC 中则不是（p=0.13）。因此，肿瘤浸润性 FOXP3+Treg 频率高与早期 T 分期相关，并独立预测 MMR 有效的 CRC 患者的疾病特异性生存率改善。
