title: Critical role of spatial interaction between CD8⁺ and Foxp3⁺ cells in human gastric cancer: the distance matters.
abstract: OBJECTIVE
  In various cancer types, an abundance of FoxP3(+) regulatory T cells (Treg) has been associated with an unfavorable outcome. Yet, the role of Treg on cancer immunity has been shown to be complex. In single cell marker technique, other tumor-infiltrating lymphocytes (TILs) such as cytotoxic CD8(+) T cells (CTL) also influenced prognosis. This study for the first time investigates the concurrent spatial distribution pattern of CD8(+) and FoxP3(+) TILs and their prognostic impact in human gastric cancer.
  
  
  METHODS
  Tumor tissue microarrays of 50 patients with surgically treated adenocarcinoma of the cardia were studied. An immunohistochemical double staining of CD8(+) and FoxP3(+) TILs was performed. Cell counts and cell-to-cell distances in tumor epithelium and stroma were evaluated with image-processing software. Metastasis-free survival, no-evidence-of-disease survival, and overall survival were investigated (mean follow-up time 6.9 years).
  
  
  RESULTS
  High intraepithelial infiltration of CD8(+) and FoxP3(+) TIL was associated with the improved 10-year metastasis-free survival (83 vs. 54%, p = 0.04 and 85 vs. 59%, p = 0.09, respectively). Considering cell-to-cell distance and comparing patients with functional (30-110 μm) versus nonfunctional distances of CD8(+) and FoxP3(+) TILs, 10-year survival rates differed between 89 and 55% (p = 0.009), respectively.
  
  
  CONCLUSIONS
  Prognostic influence of tumor-infiltrating immune cells in gastric cancer critically depends on their cell-to-cell distance. FoxP3(+) TILs must be located within a distance between 30 and 110 μm of CD8(+) T cells to positively impact on prognosis.
authors.affiliation: Department of Radiation Oncology of the University Hospitals, Friedrich-Alexander-University of Erlangen-Nürnberg, Universitätsstraße 27, 91054, Erlangen, Germany.
authors.forename: Anita
authors.initials: A
authors.lastname: Feichtenbeiner
authors.forename: Matthias
authors.initials: M
authors.lastname: Haas
authors.forename: Maike
authors.initials: M
authors.lastname: Büttner
authors.forename: Gerhard G
authors.initials: GG
authors.lastname: Grabenbauer
authors.forename: Rainer
authors.initials: R
authors.lastname: Fietkau
authors.forename: Luitpold V
authors.initials: LV
authors.lastname: Distel
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000032:analysis*; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D013274:Stomach Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors