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

Abstract

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 ¼ .004) and Treg intratumoral localization (P ¼ .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

Immunological aspect of the liver and metastatic uveal melanoma

“…While UM cells possess tumor-associated antigens and tumor-infiltrating CD4 + and CD8 + cells are present in the primary UM, Treg cells are also present in the tumor. One study has identified that the frequency of CD4 + , forkhead box P3 (FoxP3) + Treg cells within primary UM is correlated with the development of systemic metastasis [10] . The presence of Treg cells and cyclooxygenase-2 expression in the tumors is especially correlated with poor prognosis [10] .…”

“…One study has identified that the frequency of CD4 + , forkhead box P3 (FoxP3) + Treg cells within primary UM is correlated with the development of systemic metastasis [10] . The presence of Treg cells and cyclooxygenase-2 expression in the tumors is especially correlated with poor prognosis [10] . In terms of the role of NK cells in primary UM, down-regulation of HLA class I, which is a common mechanism for evading CD8 + cells, renders tumors more susceptible to NK cell-mediated lysis.…”

Inflammation in uveal melanoma

“…In many studies, Treg accumulation within tumours is a marker for poor clinical outcome. 37 When studying uveal melanoma, two studies found no association between Treg numbers in uveal melanoma and survival, 38,39 although the presence of Tregs has been associated with the extent of cyclooxygenase-2 expression, a bad prognostic factor. We do not yet know whether these cells are present in metastases and contribute to local immunosuppression in the liver.…”

The Prognostic Value of FoxP3+ Tumor-Infiltrating Lymphocytes in Cancer: A Critical Review of the Literature

“…In the end, we reviewed 58 studies encompassing 16 different cancer types (Table 1), including bladder (19), breast (21)(22)(23)(24)(25)(26)(27)(28), cervical (29,30), colorectal (12,(31)(32)(33)(34)(35)(36)(37)(38)(39), endometrial (40)(41)(42), gastric (14,(43)(44)(45)(46), head and neck (47), hepatocellular (48)(49)(50)(51)(52), lung (53,54), melanoma (55)(56)(57)(58), mesothelial (59), oral (4,(60)(61)(62)(63), ovarian (2,3,…”