title: Intense Foxp3+ CD25+ regulatory T-cell infiltration is associated with high-grade cutaneous squamous cell carcinoma and counterbalanced by CD8+/Foxp3+ CD25+ ratio.
abstract: BACKGROUND
  Recent reports have revealed the therapeutic potential of cell-mediated immunity in neoplasms such as cutaneous squamous cell carcinoma (SCC).
  
  
  OBJECTIVE
  To define the antigenic coexpression of regulatory T cells (Tregs) and plasmacytoid dendritic cells (pDCs) and assess the CD8(+) /Foxp3(+) CD25(+) cell ratio at peritumoral and intratumoral levels in order to investigate a correlation with the aggressiveness of SCC tumours.
  
  
  METHODS
  We evaluated the content and distribution of Foxp3(+) CD25(+) Treg and CD123(+) pDC infiltration and assessed CD8(+) /Foxp3(+) CD25(+) cell ratio at peritumoral and intratumoral levels in 40 SCCs (20 well-differentiated, G1; and 20 moderately to poorly differentiated, G2-G3) to investigate a correlation with their aggressiveness. We determined the profiles of Tregs and CD123(+) cells; immunostained for CD4, CD8, CD123, interleukin (IL)-1 and transforming growth factor (TGF)-β1; and unequivocally double stained for Foxp3CD25.
  
  
  RESULTS
  Peritumorally, CD4, CD8 and Foxp3 expression showed no difference between the two groups. CD123(+) cells were fewer in G2-G3 (P = 0·0005), while Foxp3(+) CD25(+) cells were more numerous (P = 0·0005). The Foxp3(+) CD25(+) /Foxp3(+) ratio was higher in G2-G3 cases (P = 0·0005), confirming the trend in this group of activated T lymphocytes towards total Treg Foxp3(+) cells, while the CD8(+) /Foxp3(+) CD25(+) ratio was higher in G1 (P = 0·0005). Intratumorally, CD4(+) and CD8(+) cells infiltrated G2-G3 (P = 0·048) more than G1 (P = 0·004), whereas almost all cells were CD123 negative. Regarding Foxp3CD25, TGF-β1 and IL-10, they were less expressed in G1, whereas they were positive in G2-G3 (P < 0·05). The CD8(+) /Foxp3(+) CD25(+) ratio was similar to that observed in peritumoral infiltration.
  
  
  CONCLUSIONS
  Our data suggest that intratumoral recruitment of Tregs, high expression of TGF-β1 and IL-10, almost negative CD123+, and a low CD8(+) /Foxp3(+) CD25(+) T-cell ratio may contribute to the aggressiveness of cutaneous SCC, as already evidenced for other solid tumours.
authors.affiliation: Department of Health Sciences, Medical School, University of Piemonte Orientale 'A. Avogadro', 28100, Novara, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Azzimonti
authors.forename: E
authors.initials: E
authors.lastname: Zavattaro
authors.forename: M
authors.initials: M
authors.lastname: Provasi
authors.forename: M
authors.initials: M
authors.lastname: Vidali
authors.forename: A
authors.initials: A
authors.lastname: Conca
authors.forename: E
authors.initials: E
authors.lastname: Catalano
authors.forename: L
authors.initials: L
authors.lastname: Rimondini
authors.forename: E
authors.initials: E
authors.lastname: Colombo
authors.forename: G
authors.initials: G
authors.lastname: Valente
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology*; D016753:Interleukin-10 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; D016753:Interleukin-10