title: Perturbations of both nonregulatory and regulatory FOXP3+ T cells in patients with malignant melanoma.
abstract: BACKGROUND
  'FOXP3+ regulatory T cells' (Tregs) are reported to be increased in tumour-bearing hosts including patients with melanoma, leading to tumour immune suppression. However, this idea is challenged by recent evidence that the 'FOXP3+ Treg' fraction in fact contains activated 'nonregulatory' T cells. Also, FOXP3+ T cells are reported to have functionally and kinetically distinct subsets.
  
  
  OBJECTIVE
  To investigate whether either or both of regulatory and 'nonregulatory' FOXP3+ T cells are perturbed in patients with melanoma.
  
  
  METHODS
  FOXP3+ T cells were classified into three subsets, namely CD45RO+FOXP3(low) nonregulatory T cells, CD45RO+FOXP3(high) effector Tregs, and CD45RO-FOXP3(low) naïve Tregs, according to their expression levels of FOXP3 and CD45RO. The percentage and cytokine production of these FOXP3+ T-cell subsets were assessed by flow cytometry.
  
  
  RESULTS
  Both regulatory and nonregulatory T cells were increased in patients with melanoma. Moreover, we found three unexpected perturbations in FOXP3+ T-cell subsets: (i) patients with melanoma showed higher frequencies of FOXP3(low) nonregulatory T cells, which decreased and normalized after tumour removal; (ii) FOXP3(low) naïve Tregs containing higher frequencies of interferon-γ+ cells increased with tumour progression; and (iii) CD45RO+FOXP3(high) effector Tregs were pronouncedly infiltrated around tumour tissues.
  
  
  CONCLUSIONS
  These findings demonstrate that patients with melanoma have distinct and differential perturbation of both regulatory and nonregulatory FOXP3+ T cells. The degree of perturbation is associated with tumour burden and progression, suggesting that the perturbation reflects fundamental pathophysiological processes in patients with melanoma. The presented analysis provides a practical approach to investigate the immunological environment of cancer patients.
authors.affiliation: Department of Dermatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo Kyoto 606-8507, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Fujii
authors.forename: A
authors.initials: A
authors.lastname: Arakawa
authors.forename: A
authors.initials: A
authors.lastname: Kitoh
authors.forename: M
authors.initials: M
authors.lastname: Miyara
authors.forename: M
authors.initials: M
authors.lastname: Kato
authors.forename: S
authors.initials: S
authors.lastname: Kore-eda
authors.forename: S
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Miyachi
authors.forename: M
authors.initials: M
authors.lastname: Tanioka
authors.forename: M
authors.initials: M
authors.lastname: Ono
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016207:Cytokines / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006801:Humans; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000097:blood / Q000276:immunology*; D008875:Middle Aged; D012878:Skin Neoplasms / Q000097:blood / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D055815:Young Adult
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D017493:Leukocyte Common Antigens