Intratumoral forkhead box P3‐positive regulatory T cells predict poor survival in cyclooxygenase‐2–positive uveal melanoma

BACKGROUND: Forkhead box P3 (FOXP3)-positive regulatory T cells (Tregs) are key mediators of peripheral tolerance and suppress efficient antitumor responses. Prostaglandin E(2) (PGE(2)) produced by inducible cyclooxygenase-2 (COX-2) can lead to Treg induction. COX-2 expression has been linked to tumorigenesis and growth in various malignancies. The objective of the current study was to investigate whether Tregs infiltrate uveal melanomas (UMs) and whether their prevalence is linked to COX-2 expression and the prediction of overall survival (OS). METHODS: One hundred patients who underwent enucleation after they were diagnosed with UM were included in the study. Immunohistochemical staining with monoclonal anti-FOXP3, anti-CD4, and anti-COX-2 antibodies was performed, and immunoreactivity was assessed. Correlations of COX-2 expression with the presence of Tregs, established clinicopathologic parameters, and OS were evaluated in univariate and multivariate analyses. RESULTS: High expression of COX-2 was predictive of shortened OS. FOXP3-positive Tregs were detectable in 24% of UMs and were restricted to malignant tissue. The extent of COX-2 expression was associated significantly with Treg prevalence (P = .004) and Treg intratumoral localization (P = .005). Intratumoral Tregs (but not the prevalence of Tregs) were independent marker for worse OS with a hazard ratio of 5.36 in patients with COX-2-positive tumors. CONCLUSIONS: The current results demonstrated that high COX-2 expression is associated with OS and Treg prevalence in UM. These findings are in line with the observations that COX-2/PGE(2) induces Tregs and that Tregs may alter antitumor responses, resulting in a negative effect on the clinical disease course. Intratumoral Tregs are an independent prognostic marker for COX-2-positive UM, and these results put COX-2 inhibitors and Treg depletion into the spotlight of potential novel treatment modalities for patients with UM.