title: Differential tumor infiltration by T-cells characterizes intrinsic molecular subtypes in breast cancer.
abstract: Molecular subtypes of breast cancer and presence of tumor-infiltrating immune cells have both been implicated as important predictive and prognostic factors for improved risk stratification and treatment individualization of breast cancer patients. Their association, however, has not been studied in detail. The aim of this study was to evaluate the expression of the T cell markers CD8, FoxP3, CD3 and ζ-chain in molecular subtypes of the invasive margin and tumor center of breast cancer and corresponding sentinel nodes and to deduct prognostic information from these findings.
  
  
  
  Tumor and sentinel node sections from 177 patients with primary, invasive, unilateral early-stage breast cancer were stained by immunohistochemistry and T-cell phenotypes quantified manually. Clinical data were collected from medical records.
  
  
  
  The degree of T-cell infiltration and expression of all markers differed significantly among the molecular subtypes, being highest in non-luminal, more aggressive tumors: more T-cell infiltration and higher expression of all markers were associated with hormone receptor negativity, higher proliferation and higher histological grades, but also with larger tumor size. Basal-like tumors, and most remarkably their tumor centers, hosted the highest number of FoxP3+ T-cells with an unfavorable ratio to cytotoxic CD8+ T-cells. T-cell infiltration was generally higher in the invasive margin than the tumor center. A scoring system based on densities of CD3 and CD8 could significantly separate molecular subtypes (p < 0.001).
  
  
  
  Thus, immunological patterns with functional implications within each subtype are associated with prognostic factors. These findings should be further validated in studies using larger patient populations and longer follow-up.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Miyan
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.|Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Schmidt-Mende
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Kiessling
authors.affiliation: Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Poschke
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. janamarit@yahoo.com.|Department of Breast and Endocrine Surgery, P9:03, Karolinska University Hospital, 17176, Stockholm, Sweden. janamarit@yahoo.com.
authors.forename: J
authors.identifier: 0000-0001-9518-0902
authors.initials: J
authors.lastname: de Boniface
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001943:Breast Neoplasms / Q000145:classification* / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D015415:Biomarkers
keywords: Breast neoplasms; Cytotoxic T-lymphocytes; Molecular subtypes; Regulatory T-lymphocytes; Tumor-infiltrating lymphocytes