title: Immunomodulation of FOXP3+ regulatory T cells by the aromatase inhibitor letrozole in breast cancer patients.
abstract: OBJECTIVE
  We have shown previously that tumor infiltration by FOXP3+ regulatory T cells (Treg) is associated with increased relapse and shorter survival of patients with both in situ and invasive breast cancer. Because estrogen regulates Treg numbers in mice and promotes the proliferation of human Tregs, we hypothesized that blocking estrogen receptor-alpha signaling would abrogate Tregs and be associated with response to hormonal therapy and increased survival.
  
  
  METHODS
  FOXP3+ Tregs were quantified in tumor samples collected at baseline by incisional biopsy and after 6 months at definitive surgery in 83 elderly breast cancer patients (T2-4 N0-1) enrolled in a randomized phase II trial based on 6 months of primary letrozole (2.5 mg/d) or 6 months of letrozole plus oral "metronomic" cyclophosphamide (50 mg/d).
  
  
  RESULTS
  Treg number ranged from 0 to 380 (median, 30) before treatment and from 0 to 300 (median, 8) after treatment. There was a significant reduction in Tregs in letrozole and letrozole-cyclophosphamide patients (P < 0.0001 and P < 0.002, respectively) after treatment. Treg number at residual histology was inversely related with response (P < 0.03 and P = 0.50, respectively) and a greater Treg reduction was observed in responding patients (P < 0.03).
  
  
  CONCLUSIONS
  This study suggests that aromatase inhibitors may have an indirect antitumor mechanism of action through reducing Tregs in breast tumors and may be of use in estrogen receptor-alpha-negative tumors in combination with immunotherapy approaches.
authors.affiliation: Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Daniele
authors.initials: D
authors.lastname: Generali
authors.forename: Gaynor
authors.initials: G
authors.lastname: Bates
authors.forename: Alfredo
authors.initials: A
authors.lastname: Berruti
authors.forename: Maria P
authors.initials: MP
authors.lastname: Brizzi
authors.forename: Leticia
authors.initials: L
authors.lastname: Campo
authors.forename: Simone
authors.initials: S
authors.lastname: Bonardi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bersiga
authors.forename: Giovanni
authors.initials: G
authors.lastname: Allevi
authors.forename: Manuela
authors.initials: M
authors.lastname: Milani
authors.forename: Sergio
authors.initials: S
authors.lastname: Aguggini
authors.forename: Luigi
authors.initials: L
authors.lastname: Dogliotti
authors.forename: Alison H
authors.initials: AH
authors.lastname: Banham
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Alberto
authors.initials: A
authors.lastname: Bottini
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D002452:Cell Count; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000494:pharmacology*; D011237:Predictive Value of Tests; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D016896:Treatment Outcome; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D047072:Aromatase Inhibitors; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole