title: FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy.
abstract: BACKGROUND
  Recent studies have demonstrated a direct involvement of B7-H1, PD-1 and FOXP3 molecules in the immune escape of cancer. B7-H1 is an inhibitory molecule that binds to PD-1 on T lymphocytes, while FOXP3 is a marker for regulatory T cells (Tregs). We have previously demonstrated the association of B7-H1-expressing T infiltrating lymphocytes (TIL) with high-risk breast cancer patients while other studies reported the involvement of FOXP3+ Tregs as a bad prognostic factor in breast tumors. Although the co-existence between the two types of cells has been demonstrated in vitro and animal models, their relative infiltration and correlation with the clinicopathological parameters of cancer patients have not been well studied. Therefore, we investigated TIL-expressing the B7-H1, PD-1, and FOXP3 molecules, in the microenvironment of human breast tumors and their possible association with the progression of the disease.
  
  
  METHODS
  Using immunohistochemistry, tumor sections from 62 breast cancer patients were co-stained for B7-H1, PD-1 and FOXP3 molecules and their expression was statistically correlated with factors known to be involved in the progression of the disease.
  
  
  RESULTS
  A co-existence of B7-H1+ T lymphocytes and FOXP3+ Tregs was evidenced by the highly significant correlation of these molecules (P < .0001) and their expression by different T lymphocyte subsets was clearly demonstrated. Interestingly, concomitant presence of FOXP3+ Tregs, B7-H1+ and PD-1+ TIL synergistically correlated with high histological grade (III) (P < .001), estrogen receptor negative status (P = .017), and the presence of severe lymphocytic infiltration (P = .022).
  
  
  CONCLUSIONS
  Accumulation of TIL-expressing such inhibitory molecules may deteriorate the immunity of high-risk breast cancer patients and this should encourage vigorous combinatorial immunotherapeutic approaches targeting Tregs and B7-H1/PD-1 molecules.
authors.affiliation: Tumor Immunology Section, King Faisal Specialist Hospital and Research Center, P,O, Box 3354, Riyadh 11211, Saudi Arabia. hghebeh@kfshrc.edu.sa
authors.forename: Hazem
authors.initials: H
authors.lastname: Ghebeh
authors.forename: Eman
authors.initials: E
authors.lastname: Barhoush
authors.forename: Asma
authors.initials: A
authors.lastname: Tulbah
authors.forename: Naser
authors.initials: N
authors.lastname: Elkum
authors.forename: Taher
authors.initials: T
authors.lastname: Al-Tweigeri
authors.forename: Said
authors.initials: S
authors.lastname: Dermime
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000096:biosynthesis*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D060890:B7-H1 Antigen; D001943:Breast Neoplasms / Q000097:blood* / Q000628:therapy*; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D007167:Immunotherapy / Q000379:methods*; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor; D011960:Receptors, Estrogen / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011960:Receptors, Estrogen