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.