The ratios of CD8+ T cells to CD4+CD25+ FOXP3+ and FOXP3- T cells correlate with poor clinical outcome in human serous ovarian cancer

PLoS One. 2013 Nov 14;8(11):e80063. doi: 10.1371/journal.pone.0080063. eCollection 2013.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / pathology*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology*
  • Cystadenocarcinoma, Serous / genetics
  • Cystadenocarcinoma, Serous / immunology
  • Cystadenocarcinoma, Serous / mortality
  • Cystadenocarcinoma, Serous / pathology*
  • Female
  • Forkhead Transcription Factors
  • Gene Expression
  • Humans
  • Immunophenotyping
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Lymphocyte Count
  • Middle Aged
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / mortality
  • Ovarian Neoplasms / pathology*
  • Ovary / immunology
  • Ovary / pathology
  • Prognosis
  • Survival Analysis
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / pathology*


  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • IL2RA protein, human
  • Interleukin-2 Receptor alpha Subunit