Tumor-Infiltrating Foxp3+ Regulatory T Cells are Correlated with Cyclooxygenase-2 Expression and are Associated with Recurrence in Resected Non-small Cell Lung Cancer

Abstract

Cyclooxygenase-2 (COX-2) is constitutively overexpressed in a variety of epithelial malignancies and is usually associated with a poor prognosis. COX-2-derived prostaglandin E2 transforms CD4+CD25+ T regulatory (Treg) cells (Tregs), and Tregs are thought to moderate the antitumor immune response. Herein, we investigated the prognostic value of tumor-infiltrating Treg cells and their correlation with COX-2 expression in resected non-small cell lung cancer (NSCLC). Intratumoral COX-2 and Treg expression were retrospectively assessed using immunohistochemistry in paraffin-embedded samples from 100 patients who had undergone complete resections for NSCLC. The expressions of COX-2 and Foxp3, which was most specific Treg cell marker, were compared with the clinicopathological variables, and the correlation between Foxp3+ Tregs and COX-2 expression was analyzed. The recurrence-free survival (RFS) of patients with elevated COX-2 expression was significantly worse than that of patients without COX-2 expression. Tumor-infiltrating Foxp3-positive lymphocytes were positively correlated with COX-2 expression. The median count for Foxp3-positive lymphocytes was 3 (minimum-maximum, 0-24) in 10 high-power fields. The RFS of patients with tumors containing >or=3 Foxp3-positive cells (Foxp3 expression group) was significantly worse than that of patients with tumors containing <3 Foxp3-positive cells. In a multivariate analysis, only nodal status was an independent predictor of a significantly shorter RFS. However, in node-negative NSCLC, Foxp3 expression was an independent predictor of a significantly shorter RFS. Tumor-infiltrating Foxp3+ Tregs were positively correlated with intratumoral COX-2 expression and were associated with a worse RFS, especially among patients with node-negative NSCLC.