Ovarian cancer tumor infiltrating T-regulatory (Treg ) cells are associated with a metastatic phenotype

Abstract Objective The objective of this study was to examine the clinicopathologic correlates of T-regulatory (Treg ) cell infiltration in serous ovarian cancers and to define gene signatures associated with high Treg s. Methods Tumor infiltrating Treg and cytotoxic T-cells (CTLs) were quantitated in 232 primary serous ovarian cancers by immunostaining for FOXP3 and CD8. Expression microarray analysis was performed in a subset of 48 advanced cancers with the highest and lowest numbers of infiltrating Treg s and a genomic signature was developed using binary regression. ANOVA analysis was performed to assess the most differentially expressed genes and these genes were further assessed using Ingenuity Pathway Analysis (IPA) software. Results High Treg infiltration in ovarian cancers was associated with high grade ( p < 0.0001), advanced stage ( p = 0.004) and suboptimal debulking ( p < 0.04), but not with survival. In contrast, high tumor infiltrating CD8 CTL infiltration was associated with favorable survival (median survival 48.7 vs. 34.6 months, p = 0.01). A microarray-based genomic signature for high tumor-infiltrating Treg cells had a 77% predictive accuracy using leave-one-out cross-validation. ANOVA of microarray data revealed the antigen presentation pathway as the most differentially expressed canonical pathway ( p < 0.00001) between cancers with high and low Treg cells. Conclusions These data suggest that there may be an association between increased Treg cell infiltration in ovarian cancers and advanced stage. Increased Treg infiltration is characterized by a genomic signature enriched with several immunologic pathway genes. Therapeutic strategies that reduce tumor infiltrating Treg cells are under investigation and may prove useful in ovarian cancers with high numbers of these cells.