Intense Foxp3⁺CD25⁺ regulatory T-cell infiltration is associated with high-grade cutaneous squamous cell carcinoma and counterbalanced by CD8⁺/Foxp3⁺CD25⁺ ratio

Background Recent reports have revealed the therapeutic potential of cell-mediated immunity in neoplasms such as cutaneous squamous cell carcinoma (SCC). Objectives 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.