title: Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer.
abstract: OBJECTIVE
  To determine the prognostic significance of FOXP3(+) lymphocyte (Treg) density in colorectal cancer compared with conventional histopathologic features and with CD8(+) and CD45RO(+) lymphocyte densities.
  
  
  METHODS
  Tissue microarrays and immunohistochemistry were used to assess the densities of CD8(+), CD45RO(+), and FOXP3(+) lymphocytes in tumor tissue and normal colonic mucosa from 967 stage II and stage III colorectal cancers. These were evaluated for associations with histopathologic features and patient survival.
  
  
  RESULTS
  FOXP3(+) Treg density was higher in tumor tissue compared with normal colonic mucosa, whereas CD8(+) and CD45RO(+) cell densities were lower. FOXP3(+) Tregs were not associated with any histopathologic features, with the exception of tumor stage. Multivariate analysis showed that stage, vascular invasion, and FOXP3(+) Treg density in normal and tumor tissue were independent prognostic indicators, but not CD8(+) and CD45RO(+). High FOXP3(+) Treg density in normal mucosa was associated with worse prognosis (hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.13; P = .019). In contrast, a high density of FOXP3(+) Tregs in tumor tissue was associated with improved survival (HR = 0.54; 95% CI, 0.38 to 0.77; P = .001).
  
  
  CONCLUSIONS
  FOXP3(+) Treg density in normal and tumor tissue had stronger prognostic significance in colorectal cancer compared with CD8(+) and CD45RO(+) lymphocytes. The finding of improved survival associated with a high density of tumor-infiltrating FOXP3(+) Tregs in colorectal cancer contrasts with several other solid cancer types. The inclusion of FOXP3(+) Treg density may help to improve the prognostication of early-stage colorectal cancer.
authors.affiliation: School of Surgery and Biostatistics Unit, Cancer Trials, Western Australian Institute for Medical Research, University of Western Australia, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Salama
authors.forename: Michael
authors.initials: M
authors.lastname: Phillips
authors.forename: Fabienne
authors.initials: F
authors.lastname: Grieu
authors.forename: Melinda
authors.initials: M
authors.lastname: Morris
authors.forename: Nik
authors.initials: N
authors.lastname: Zeps
authors.forename: David
authors.initials: D
authors.lastname: Joseph
authors.forename: Cameron
authors.initials: C
authors.lastname: Platell
authors.forename: Barry
authors.initials: B
authors.lastname: Iacopetta
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D017493:Leukocyte Common Antigens