FoxP3(+) and IL-17(+) cells are correlated with improved prognosis in cervical adenocarcinoma

Abstract

Cervical adenocarcinoma comprises approximately 15 % of cervical cancer cases. This histological subtype has different characteristics than cervical squamous cell carcinoma, which may influence disease progression. To study whether the infiltration of T cell subpopulations was correlated with cervical adenocarcinoma patient survival, similar to squamous cell carcinoma, the tumor-infiltrating T cells, Tregs, Th17 cells and IL-17(+) cell frequencies were analyzed in a cohort of cervical adenocarcinoma patients (n = 67). Intraepithelial, stromal and total cell frequencies were scored using triple immunofluorescence. The majority of Tregs were present in the tumor stroma, while other T cells and IL-17(+) cells infiltrated the tumor epithelium three times more frequently. A high total number of Tregs were significantly correlated with improved disease-specific and disease-free survival (p = 0.010, p = 0.007). Within the tumor epithelium, a high T cell frequency was significantly correlated with improved disease-free survival (p = 0.034). In particular, a low number of both Tregs and IL-17(+) cells were correlated with poor disease-specific survival (p = 0.007). A low number of Tregs combined with Th17 cells present were also correlated with poor survival (p = 0.018). An increased number of IL-17(+) cells were significantly correlated with the absence of vaso-invasion (p = 0.001), smaller tumor size (p = 0.030) and less infiltration depth (p = 0.021). These results suggest that Tregs and IL-17(+) cells represent a beneficial immune response, whereas Th17 cells might represent a poor response in cervical adenocarcinoma. This contrasts with the correlations described in squamous cell carcinoma, suggesting that the local immune response in cervical adenocarcinoma contributes differently to tumor growth than in squamous cell carcinoma.

Fig. 1

Representative image of a cervical adenocarcinoma specimen stained by triple immunofluorescence for IL-17 (a), CD3 (b) and FoxP3 (c), with the combined staining together with DAPI counterstain (gray) shown in (d). The arrow indicates a cell double positive for IL-17 and CD3. Different CD3/FoxP3 double positive cells are present

Fig. 2

Kaplan–Meier survival curves for a high versus low number of total CD3⁺ T cells (a, d), CD3⁺FoxP3⁺ Tregs (b, e) and CD3⁺FoxP3⁻ T cells (c, f) are shown for disease-specific (a–c) and disease-free survival (d–f)

Fig. 3

Kaplan–Meier survival curves for a high versus low number of CD3⁺ cells (a, d), CD3⁺FoxP3⁺ Tregs (b, e) and CD3⁺FoxP3⁻ T cells (c, f) infiltrating in the tumor epithelium (IE) are shown for disease-specific (a–c) and disease-free survival (d–f)

Fig. 4

Kaplan–Meier survival curves for disease-specific survival based on a high number of Tregs compared with a low number of Tregs combined with high or low IL-17⁺ cells (a) or the absence or the presence of Th17 cells (b)

Fig. 5

Correlation between the number of total non-Th17 IL-17⁺ cells and vaso-invasion is shown in a. The p value was calculated using the Wilcoxon Mann–Whitney test. The correlations between the number of non-Th17 IL-17⁺ cells and the continuous variables tumor infiltration depth (b) and tumor size (c) were calculated using the Spearman’s rank correlation rho test