The correlation between tumor-infiltrating Foxp3+ regulatory T cells and cyclooxygenase-2 expression and their association with recurrence in resected head and neck cancers

Abstract

The aim of this study was to investigate the correlation between tumor-infiltrating CD4+ CD25(high) Foxp3+ naturally occurring regulatory T cells (Foxp3+ nTregs) and cyclooxygenase-2 (COX-2) expression and their association with local recurrence in resected head and neck cancers. Intratumoral COX-2 and Foxp3+ nTregs expressions were retrospectively assessed using immunohistochemistry. Associations between the clinicopathological characteristics and either intratumoral COX-2 expression or number of Foxp3+ nTregs were tested using the Chi-square test. The correlation between the number of Foxp3+ nTregs and COX-2 expression was tested using Spearman's rank correlation test. Associations between recurrence-free survival (RFS) and either intratumoral COX-2 expression or number of Foxp3+ nTregs were calculated using the Kaplan-Meier method, and factors that may influence the RFS were analyzed by Cox regression. The five-year RFS for all patients was 35.09%. Patient clinicopathological characteristics had no relationship with intratumoral COX-2 expression or the number of Foxp3+ nTregs. However, a positive correlation between intratumoral COX-2 expression and the number of Foxp3+ nTregs was observed (P < 0.001). The RFS of patients with elevated COX-2 expression was significantly worse than that of patients without intratumoral COX-2 expression (P = 0.0228). The RFS of patients with tumors containing >6 Foxp3+ cells was significantly worse than that of patients with tumors containing ≤6 Foxp3+ cells (P = 0.0020). However, by Cox regression analysis, the RFS of all patients was not influenced by intratumoral COX-2 expression (P = 0.100) or the number of Foxp3+ nTregs (P = 0.071). Tumor-infiltrating CD4+ CD25(high) Foxp3+ nTregs were positively correlated with intratumoral COX-2 expression and were associated with a worse RFS in univariate analysis.

Clinical relevance of immune parameters in the tumor microenvironment of head and neck cancers

“…In the oral cavity, FoxP3+ TIL have been shown to be unfavorable when in high numbers intratumorally and peritumorally, which suggests that oral cavity tumors prosper in environments where the inflammatory response is dampened. The opposite correlation with clinical outcome, however, was seen in oropharyngeal tumors and both positive and negative associations were shown in studies of combined head and neck cancer subsites.…”

“…Other T‐lymphocyte populations, CD3+, CD4+, and CD25+, have also demonstrated favorable features when observed in higher numbers . Interestingly, the effect of FoxP3+CD4+T‐reg cells has been shown to be beneficial and detrimental in an equal number of studies. FoxP3+ cells may behave differently in different anatomic subsites, which might explain this phenomenon.…”

Clinicopathological and prognostic significance of cyclooxygenase-2 expression in head and neck cancer: A meta-analysis

“…9 studies were excluded as they did not provide sufficient data for extracting odds ratio (OR) or hazard ratio (HR) or 95% confidence intervals (CI) [28–36], leaving 29 studies that fulfilled the eligibility criteria [22–27, 37–59] (Table 1). Four studies reported no site-specific HNC [24, 54–57] and others recorded site-specific HNC. There were 7, 6 and 9 studies focused on oral cancer (OC) [22, 25, 27, 37–40], laryngeal cancer (LC) [41–46] and nasopharyngeal cancer (NPC) [23, 26, 47–53], respectively.…”

The Tumor Microenvironment Contribution to Development, Growth, Invasion and Metastasis of Head and Neck Squamous Cell Carcinomas

“…Immunohistochemical studies revealed that COX-2 overexpression was positively correlated with the number of tumor-infiltrating Foxp3+ regulatory T cells in the local microenvironment of HNSCC. This suggests that COX-2 facilitated the expansion of the regulatory T cells through PGE 2 150.…”