title: Mechanisms of tumor immune escape in triple-negative breast cancers (TNBC) with and without mutated BRCA 1.
abstract: OBJECTIVE
  Triple negative breast cancers (TNBC) are associated with an adverse outcome, although these tumors are sensitive to chemotherapy. In part, this phenomenon could be caused by tumor immune escape. The current study investigates immunogenicity of TNBC cells in vitro and the presence of immunosuppressive factors in the tumor microenvironment (pAKT and B7H1 expression, infiltration with regulatory T cells, [Tregs]).
  
  
  METHODS
  Natural killer (NK)-cell induced lysis was evaluated in estrogen receptor (ER) positive MCF 7 breast cancers, in MDA-MB231 and MDA-MB468 and in HCC-1937 (BRCA 1 mutated) and HCC-1806 TNBC cells. Expression of pAKT, B7H1 and infiltration with Tregs were determined by immunohistochemistry in human specimens of benign and malignant breast disease.
  
  
  RESULTS
  NK-cell induced lysis was significantly increased (p < 0.05) in four TNBC cell lines compared to ER + MCF 7 cells. Fibroadenomas and mastectomy samples were not infiltrated with Tregs. Infiltration with Tregs was 0.92 ± 0.21 in ER/PR + breast cancers and significantly higher in TNBC without (2.30 ± 0.34) and also significantly higher with mutation of BRCA 1 (2.10 ± 0.34). Expression of pAKT was absent in benign controls and 1.23 ± 0.36 in ER/PR + breast cancers, 1.78 ± 0.40 in TNBC without and 2.40 ± 0.30 with mutated BRCA 1. No significant differences of B7H1 expression occurred among the breast cancer subgroups.
  
  
  CONCLUSIONS
  TNBC cell stimulate the NK-cell immune response significantly stronger than ER positive breast cancer cells. This could explain why infiltration with immunosuppressive Tregs is increased in human specimens of TNBC with and without mutated BRCA 1. Accordingly, immunomodulatory treatment strategies should be further explored in TNBC.
authors.affiliation: Universitätsfrauenklinik Regensburg, Caritas Krankenhaus St Josef, Landshuter Str 65, 93053, Regensburg, Germany, joergbengel@hotmail.com.
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Engel
authors.forename: Arnd
authors.initials: A
authors.lastname: Honig
authors.forename: Michaela
authors.initials: M
authors.lastname: Kapp
authors.forename: Jens C
authors.initials: JC
authors.lastname: Hahne
authors.forename: Susanne R
authors.initials: SR
authors.lastname: Meyer
authors.forename: Johannes
authors.initials: J
authors.lastname: Dietl
authors.forename: Sabine E
authors.initials: SE
authors.lastname: Segerer
mesh_terms: D060890:B7-H1 Antigen / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D019139:Tumor Escape / Q000235:genetics*
chemical_list: D060890:B7-H1 Antigen; D019313:BRCA1 Protein; C423236:CD274 protein, human; D011960:Receptors, Estrogen; D051057:Proto-Oncogene Proteins c-akt