title: Ovarian cancer tumor infiltrating T-regulatory (T(reg)) cells are associated with a metastatic phenotype.
abstract: OBJECTIVE
  The objective of this study was to examine the clinicopathologic correlates of T-regulatory (T(reg)) cell infiltration in serous ovarian cancers and to define gene signatures associated with high T(reg)s.
  
  
  METHODS
  Tumor infiltrating T(reg) 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 T(reg)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 T(reg) 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 T(reg) 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 T(reg) cells.
  
  
  CONCLUSIONS
  These data suggest that there may be an association between increased T(reg) cell infiltration in ovarian cancers and advanced stage. Increased T(reg) infiltration is characterized by a genomic signature enriched with several immunologic pathway genes. Therapeutic strategies that reduce tumor infiltrating T(reg) cells are under investigation and may prove useful in ovarian cancers with high numbers of these cells.
authors.affiliation: Division of Gynecologic Oncology/Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Barnett
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Bean
authors.forename: Regina S
authors.initials: RS
authors.lastname: Whitaker
authors.forename: Eiji
authors.initials: E
authors.lastname: Kondoh
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Baba
authors.forename: Shingo
authors.initials: S
authors.lastname: Fujii
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Marks
authors.forename: Holly K
authors.initials: HK
authors.lastname: Dressman
authors.forename: Susan K
authors.initials: SK
authors.lastname: Murphy
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017951:Antigen Presentation; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D055815:Young Adult