The ratios of CD8+ T cells to CD4+CD25+ FOXP3+ and FOXP3- T cells correlate with poor clinical outcome in human serous ovarian cancer.
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.
Department of Immunology, Mayo Clinic, Rochester, Minnesota, United States of America.
Claudia C
CC
Preston
Matthew J
MJ
Maurer
Ann L
AL
Oberg
Daniel W
DW
Visscher
Kimberly R
KR
Kalli
Lynn C
LC
Hartmann
Ellen L
EL
Goode
Keith L
KL
Knutson
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D005260:Female; D051858:Forkhead Transcription Factors; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D018655:Lymphocyte Count; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D010053:Ovary / Q000276:immunology / Q000473:pathology; D011379:Prognosis; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology*
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit