Ovarian cancer is an immune reactive malignancy with a complex immune suppressive network that blunts successful immune eradication. This suppressive microenvironment may be mediated by recruitment or induction of CD4+ regulatory T cells (Tregs). Our study sought to investigate the association of tumor-infiltrating CD4+CD25+FOXP3+ Tregs, and other immune factors, with clinical outcome in serous ovarian cancer patients. We performed immunofluorescence and quantification of intraepithelial tumor-infiltrating triple positive Tregs (CD4+CD25 +FOXP3+), as well as CD4+CD25 +FOXP3-, CD3+ and CD8+ T cells in tumor specimens from 52 patients with high stage serous ovarian carcinoma. Thirty-one of the patients had good survival (i.e. > 60 months) and 21 had poor survival of < 18 months. Total cell counts as well as cell ratios were compared among these two outcome groups. The total numbers of CD4 +CD25+FOXP3+ Tregs, CD4+CD25 +FOXP3-, CD3+ and CD8+ cells were not significantly different between the groups. However, higher ratios of CD8+/CD4+CD25+FOXP3+ Treg, CD8 +/CD4+ and CD8/CD4+CD25+FOXP3- cells were seen in the good outcome group when compared to the patients with poor outcome. These data show for the first time that the ratios of CD8+ to both CD4 +CD25+FOXP3+ Tregs and CD4+CD25 +FOXP3- T cells are associated with disease outcome in ovarian cancer. The association being apparent in ratios rather than absolute count of T cells suggests that the effector/suppressor ratio may be a more important indicator of outcome than individual cell count. Thus, immunotherapy strategies that modify the ratio of CD4+CD25+FOXP3 + Tregs or CD4+CD25+FOXP3- T cells to CD8+ effector cells may be useful in improving outcomes in ovarian cancer.
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