Gastroenterology

Gastroenterology

Volume 137, Issue 4, October 2009, Pages 1270-1279
Gastroenterology

Clinical—Alimentary Tract
Intraepithelial Effector (CD3+)/Regulatory (FoxP3+) T-Cell Ratio Predicts a Clinical Outcome of Human Colon Carcinoma

https://doi.org/10.1053/j.gastro.2009.06.053Get rights and content

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.

Section snippets

Patient Specimens

Surgically resected TNM stage II and III primary colon adenocarcinomas (n = 160) were analyzed from patients who participated in 5-fluorouracil (5-FU)–based adjuvant chemotherapy trials conducted by the Mayo Clinic and the North Central Cancer Treatment Group. Available paraffin-embedded tumor blocks from a nonrandom subset of study participants were used. Tumor histologic grade was categorized as follows: grade 1, well differentiated; grade 2, moderately differentiated; grade 3, poorly

Study Population

TNM stage II and III (136 [85%]) primary colon adenocarcinomas (n= 160) were analyzed from patients who participated in 5-FU–based adjuvant chemotherapy trials (see Materials and Methods). After 5 years of follow-up, 70.6% of patients were alive; at 8 years, 60.6% remained alive. Details of the study population are shown in Table 1.

FoxP3+ TILs in Human Colon Carcinomas

We analyzed Tregs, identified by FoxP3+ staining, and the adaptive immune marker CD3+ in colon carcinomas (Figure 1). Further evidence that FoxP3+ TILs were Tregs

Discussion

Tregs can suppress peripheral immune responses to tumor antigens, thus maintaining immunologic tolerance2, 9 and thereby contributing to tumor progression/metastasis.3, 12 We analyzed the expression and density of FoxP3+ TILs as a specific marker of Tregs5 and CD3+ TILs as an adaptive immune marker in human colon cancers. We found that FoxP3+ TILs were significantly enriched in primary colon cancers compared with autologous normal colonic mucosa. Similar to our results in tumor tissue, Tregs in

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      However, it should be noted that although Treg infiltration is associated with poor prognosis of several gastrointestinal cancers [109], it is contradictory for CRC, at least when FoxP3 is used as Treg marker. Some studies even found that infiltration of FoxP3+ T cells is associated with a better prognosis of CRC patients [110,111]. CD4+ FoxP3+ cells are functionally heterogeneous and can be classified into subtypes that are based on expression levels of FoxP3 and the naïve T cell marker CD45RA [112].

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported in part by National Cancer Institute grant CA104683-02 (to F.A.S.) and National Cancer Institute core grant CA15083 (to the Mayo Clinic Cancer Center).

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