上皮内效应性（CD3+）/调节性（FoxP3+）T细胞比值可预测人类结肠癌的临床结局。
Intraepithelial effector (CD3+)/regulatory (FoxP3+) T-cell ratio predicts a clinical outcome of human colon carcinoma.
作者信息
Sinicrope Frank A, Rego Rafaela L, Ansell Stephen M, Knutson Keith L, Foster Nathan R, Sargent Daniel J
机构信息
Miles and Shirley Fiterman Digestive Disease Center, Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
出版信息
Gastroenterology. 2009 Oct;137(4):1270-9. doi: 10.1053/j.gastro.2009.06.053. Epub 2009 Jul 3.
BACKGROUND & AIMS: Regulatory T cells (Tregs) express the forkhead box transcription factor (FoxP3) and suppress the antitumor immune response. We investigated whether the intratumoral densities of FoxP3(+) and effector CD3(+) lymphocytes are associated with prognosis of patients with colon cancer.
METHODS
FoxP3 and CD3 expression and location were determined in stage II and III colon carcinomas (n = 160) and normal mucosa (n = 25) by immunohistochemistry; CD4 and FoxP3 were localized by dual immunofluorescence microscopy. T-cell markers were compared with pathological variables, DNA mismatch repair status, and patient survival using Cox proportional hazards models.
RESULTS
FoxP3(+) and CD3(+) T-cell densities were increased in carcinomas compared with autologous normal mucosa (P < .0001). An increase in intraepithelial FoxP3(+) cells was associated with poor tumor differentiation (P = .038), female sex (P = .028), and advanced patient age (P = .042). FoxP3(+) cell density was not prognostic, yet patients with tumors with reduced intraepithelial CD3(+) T-cell densities had reduced disease-free survival (DFS) rates (hazard ratio [HR], 1.87 [95% confidence interval, 1.10-3.16]; P = .018). A low intraepithelial CD3(+)/FoxP3(+) cell ratio predicted reduced DFS (46.2% vs 66.7% survival at 5 years; HR, 2.17 [95% confidence interval, 1.11-4.23]; P = .0205). The prognostic impact of these markers was maintained when tumors were stratified by mismatch repair status. By multivariate analysis, a low CD3(+)/FoxP3(+) cell ratio (P= .0318) and low numbers of CD3(+) T cells (P = .0397) predicted shorter DFS times and were stronger prognostic variables than tumor stage or number of lymph node metastases.
CONCLUSIONS
A low intraepithelial CD3(+)/FoxP3(+) cell ratio and reduced numbers of CD3(+) T cells were associated with shorter patient survival time, indicating the importance of an effector to Treg cell ratio in colon cancer prognosis.
背景与目的
调节性T细胞（Tregs）表达叉头框转录因子（FoxP3）并抑制抗肿瘤免疫反应。我们研究了FoxP3(+)和效应性CD3(+)淋巴细胞的肿瘤内密度是否与结肠癌患者的预后相关。
方法
通过免疫组织化学法测定160例II期和III期结肠癌及25例正常黏膜中FoxP3和CD3的表达及定位；通过双重免疫荧光显微镜对CD4和FoxP3进行定位。使用Cox比例风险模型将T细胞标志物与病理变量、DNA错配修复状态及患者生存率进行比较。
结果
与自体正常黏膜相比，癌组织中FoxP3(+)和CD3(+) T细胞密度增加（P <.0001）。上皮内FoxP3(+)细胞增加与肿瘤低分化（P =.038）、女性（P =.028）及患者高龄（P =.042）相关。FoxP3(+)细胞密度无预后价值，但肿瘤上皮内CD3(+) T细胞密度降低的患者无病生存期（DFS）率降低（风险比[HR]，1.87 [95%置信区间，1.10 - 3.16]；P =.018）。上皮内低CD3(+)/FoxP3(+)细胞比例预示DFS降低（5年生存率分别为46.2%和66.7%；HR，2.17 [95%置信区间，1.11 - 4.23]；P =.0205）。当根据错配修复状态对肿瘤进行分层时，这些标志物的预后影响依然存在。多因素分析显示，低CD3(+)/FoxP3(+)细胞比例（P =.0318）和低CD3(+) T细胞数量（P =.0397）预示DFS时间缩短，且是比肿瘤分期或淋巴结转移数量更强的预后变量。
结论
上皮内低CD3(+)/FoxP3(+)细胞比例和低CD3(+) T细胞数量与患者较短的生存时间相关，表明效应性T细胞与调节性T细胞的比例在结肠癌预后中具有重要意义。
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