title: Prognostic impact of FoxP3+ regulatory T cells in relation to CD8+ T lymphocyte density in human colon carcinomas.
abstract: BACKGROUND
  T-lymphocyte infiltration into colon carcinomas can influence clinical outcome, and interactions among T cell subsets may be more informative than either subset alone. Our objective was to examine the prognostic impact of tumor-infiltrating FoxP3(+) regulatory T cells (Tregs) in relation to cytotoxic CD8(+) T lymphocytes in patients with colon carcinomas characterized by DNA mismatch repair (MMR) status who participated in adjuvant chemotherapy trials.
  
  
  METHODS
  FoxP3(+) and CD8(+) densities in tumor epithelial and stromal compartments were analyzed by immunohistochemistry and quantified in resected, stage II and III colonic carcinomas (N = 216). Immune marker density was dichotomized at the median and categorized as high vs low. MMR status was classified as MMR deficient (dMMR) or proficient (pMMR). Cox models were adjusted for age, stage, and tumor grade.
  
  
  RESULTS
  The density of FoxP3+ infiltration was similar in tumor stroma and epithelia, whereas CD8+ was higher in stroma. The prognostic impact of FoxP3+ and CD8+ T cell infiltration was stronger in stroma vs epithelia, and the density of each marker in stroma was independently associated with improved overall survival (OS). However, the impact of FoxP3+ on survival was dependent upon CD8+ density (P interaction = 040). Among CD8+(low) tumors, FoxP3+(high) cases had significantly improved OS compared to FoxP3+(low) cases after adjustment for covariates (hazard ratio 0.43; 95% confidence interval 0.19 to 0.95; P = .030). In contrast, FoxP3+ was not prognostic among CD8+(high) tumors. FoxP3+ remained prognostic in CD8+(low) tumors after further adjustment for MMR or BRAF(V600E) mutation status. Additionally, these immune markers identified a pMMR subgroup with a similarly favorable OS as for dMMR tumors.
  
  
  CONCLUSIONS
  The prognostic impact of FoxP3+ and CD8+ T cell density are inter-dependent, whereby FoxP3+ exerts a favorable influence on survival only in colon cancers with low CD8+ infiltration.
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Harry H
authors.initials: HH
authors.lastname: Yoon
authors.forename: Jared M
authors.initials: JM
authors.lastname: Orrock
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Foster
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sinicrope
mesh_terms: D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D003110:Colonic Neoplasms / Q000175:diagnosis* / Q000276:immunology* / Q000473:pathology; D053843:DNA Mismatch Repair / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006801:Humans; D018655:Lymphocyte Count; D008297:Male; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D015415:Biomarkers; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors