title: The intratumoural subsite and relation of CD8(+) and FOXP3(+) T lymphocytes in colorectal cancer provide important prognostic clues.
abstract: BACKGROUND
  To find improved tools for prognostic evaluation in patients with colorectal cancer (CRC), we have analysed how infiltration of cytotoxic T lymphocytes (CD8(+)) and regulatory T lymphocytes (FoxP3(+)) correlates to prognosis, not only according to quantity and relation, but also to subsite within tumours of different molecular characteristics (microsatellite instability and CpG island methylator phenotype status).
  
  
  METHODS
  CD8 and FOXP3 expression was evaluated by immunohistochemistry in 426 archival tumour tissue samples from patients surgically resected for CRC. The average infiltration of CD8(+) and FOXP3(+) cells was assessed along the tumour invasive front, in the tumour centre and within the tumour epithelium (intraepithelial).
  
  
  RESULTS
  We found that infiltration of CD8(+) T lymphocytes within the tumour epithelium provided the strongest prognostic information (P<0.001). At the tumour invasive front and tumour centre, FOXP3 expression withheld the strongest association to prognosis (P<0.001), suggesting FOXP3(+) T-lymphocyte infiltration to be a better prognostic tool than CD8(+) T lymphocytes at these intratumoural subsites. We further analysed the possible prognostic impact of the relation between these T-cell subsets, finding that a high intraepithelial CD8 expression was associated with a better patient outcome, independent of FOXP3 infiltration. In groups of low intraepithelial CD8 expression, however, a high infiltration rate of FOXP3(+) cells at the tumour invasive front, significantly improved prognosis.
  
  
  CONCLUSIONS
  Analyses of intraepithelial infiltration of CD8(+) T lymphocytes, infiltration of FOXP3(+) T lymphocytes at the tumour front or centre, and the relation between these subsets, may be a valuable tool for predicting prognosis in colon cancer.
authors.affiliation: Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Ling
authors.affiliation: Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Edin
authors.affiliation: Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
authors.forename: M L
authors.initials: ML
authors.lastname: Wikberg
authors.affiliation: Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden.
authors.forename: Å
authors.initials: Å
authors.lastname: Öberg
authors.affiliation: Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Palmqvist
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D000368:Aged; D000369:Aged, 80 and over; D016827:CD8 Antigens / Q000032:analysis*; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000473:pathology*; D003082:Colectomy; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D018899:CpG Islands; D004848:Epithelium / Q000276:immunology / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis*; D006801:Humans; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000737:chemistry / Q000473:pathology*; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009928:Organ Specificity; D011379:Prognosis; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000473:pathology*; D013602:T-Lymphocytes, Cytotoxic / Q000737:chemistry / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000473:pathology
chemical_list: D016827:CD8 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors