The Clinicopathological and Prognostic Implications of FoxP3+ Regulatory T Cells in Patients with Colorectal Cancer: A Meta-Analysis

Abstract

Background and Objective: Forkhead box P3 (FoxP3) is known as the specific marker for regulatory T lymphocytes (Tregs), which are responsible for self-tolerance and disturb the antitumor immunity. However, the prognostic implication of tumor-infiltrating FoxP3⁺ Tregs in patients with colorectal cancer (CRC) still remains controversial. The aim of this present study was to investigate the prognostic role of FoxP3⁺ Tregs in CRC through meta-analysis. Methods: PubMed, Embase and Web of Science were searched for relevant articles up to December 12, 2016. Pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated to explore the prognostic value of FoxP3⁺ Tregs in CRC. Odds ratio (OR) was calculated to investigate the correlation between FoxP3⁺ Tregs and pathological parameters. Results: A total of 18 studies comprising 3,627 patients with CRC were enrolled in our meta-analysis. The combined HR for FoxP3⁺ Tregs on cancer-specific survival was 0.70 (95% CI = 0.62-0.80, P < 0.001). High FoxP3⁺ Tregs level was also associated with favorable prognosis on overall survival (HR = 0.76, 95% CI = 0.58-1.01, P = 0.058), with P-value very close to the statistical threshold. Yet, there was no correlation between FoxP3⁺ Tregs infiltration and disease-free survival (HR = 0.83, 95% CI = 0.63-1.09, P = 0.182). Moreover, FoxP3⁺ Tregs infiltration was significantly correlated with pT stage (OR = 0.50, 95% CI = 0.39-0.65, P < 0.001), tumor grade (OR = 0.77, 95% CI = 0.61-0.98, P = 0.032), lymphatic invasion (OR = 0.25, 95% CI = 0.07-0.89, P = 0.033) and vascular invasion (OR = 0.67, 95% CI = 0.52-0.86, P = 0.001). Conclusion: The present meta-analysis suggests that high FoxP3⁺ Tregs infiltration is inclined to indicate favorable prognosis and is associated with the pathogenesis of CRC. Immunotherapy targeting Tregs in patients with CRC should be further investigated.

Keywords: FoxP3+ regulatory T lymphocytes; clinicopathological features; colorectal cancer; meta-analysis; prognostic implications.

Figure 1

Flowchart of study selection.

Figure 2

Forest plot of the HR for the association between FoxP3⁺ Tregs and CSS in patients with CRC. Frey et al. (2010) are for MMR-deficient group, MMR-proficient Test Group 1, and MMR-proficient Test Group 2, respectively. HR = 0.70, 95% CI = 0.62–0.80, P < 0.001, fixed model. FoxP3, Forkhead box P3; Tregs, regulatory T lymphocytes; CRC, colorectal cancer; CSS, cancer-specific survival; MMR, mismatch-repair; HR, hazard ratio; CI, confidence interval.

Figure 3

Forest plot of the HR for the association between FoxP3⁺ Tregs and OS in patients with CRC. HR = 0.76, 95% CI = 0.58–1.01, P = 0.058, random model. FoxP3, Forkhead box P3; Tregs, regulatory T lymphocytes; CRC, colorectal cancer; OS, overall survival; HR, hazard ratio; CI, confidence interval.

Figure 4

Forest plot of the HR for the association between FoxP3⁺ Tregs and DFS in patients with CRC. HR = 0.83, 95% CI = 0.63–1.09, P = 0.182, random model. FoxP3, Forkhead box P3; Tregs, regulatory T lymphocytes; CRC, colorectal cancer; DFS, disease-free survival; HR, hazard ratio; CI, confidence interval.

Figure 5

Sensitivity analyses and funnel plots for the publication bias of FoxP3⁺ Tregs on survival. (A) Sensitivity analysis for CSS; (B) sensitivity analysis for OS; (C) sensitivity analysis for DFS; (D) publication bias for CSS; (E) publication bias for OS; (F) publication bias for DFS. FoxP3, Forkhead box P3; Tregs, regulatory T lymphocytes; CSS, cancer-specific survival; OS, overall survival; DFS, disease-free survival.