CD8+ cytotoxic and FoxP3+ regulatory T lymphocytes serve as prognostic factors in breast cancer

Abstract

Background: There is conflicting evidence regarding the prognostic value of cytotoxic T cell infiltration in breast cancer. The aims of this study were to detect the expression levels and localization of FoxP3 and CD8 in invasive ductal carcinoma of the breast and to investigate the correlations among FoxP3⁺ regulatory T cells (Tregs), CD8⁺ cytotoxic T lymphocytes (CTLs), clinicopathological features, and prognosis in patients with breast cancer.

Methods: Immunohistochemistry was used to detect the expression levels and localization of FoxP3 and CD8. One-sample t-test, one-way analysis of variance, and Kaplan-Meier log-rank tests were used to analyze correlations between the expression levels of CD8 and FoxP3; Kaplan-Meier Log-rank test was used to analyze clinicopathological features to explore the prognostic significance of CD8 and FoxP3 in patients with breast cancer.

Results: FoxP3 expression in the tumor bed was higher than that in the stroma, while CD8 was primarily expressed in the stroma. CD8 expression was associated with favorable prognostic factors. However, FoxP3 expression and an increased ratio of total FoxP3⁺ Tregs to CD8⁺ CTLs were significantly correlated with unfavorable prognostic factors. Additionally, an increased ratio was associated with molecular subtypes (ER⁺Her2⁺, ER⁺Her2^-, ER^-Her2⁺, and ER^-Her2^-) of breast cancer. Overexpression of FoxP3 and a high FoxP3⁺/CD8⁺ ratio were correlated with poor overall survival (OS) and disease-free survival (DFS). However, CD8 expression only affected OS in patients with breast cancer.

Conclusions: Tumor-infiltrating lymphocytes are localized variously depending on the subtype. CD8⁺ CTLs were associated with a good prognosis, while FoxP3⁺ Tregs were associated with adverse outcomes in patients with breast cancer. CD8⁺ CTLs and FoxP3⁺ Tregs are potential predictive prognostic factors for patients with breast cancer.

Keywords: CD8; FoxP3; breast cancer; tumor bed; tumor stroma.

Figure 1

The expression level of CD8 and FoxP3 in tumor nest and stroma of breast cancer tissues. (A-C) are the expression level of CD8 in breast cancer tissues (A is total level of tumor nest and stroma, 100×, B is tumor nest, 400×, C is tumor stroma, 400×); (D-F) are expression level of FoxP3 in breast cancer tissues (D is total level of tumor nest and stroma, 100×, E is tumor nest, 400×, F is tumor stroma, 400×).

Figure 2

The relationship between expression levels of CD8 and DFS and OS of breast cancer patients. (A and B) are the relationship between expression level of CD8 in tumor nest and DFS and OS of breast cancer patients. (C and D) are the relationship between expression level of CD8 in tumor stroma and DFS and OS of breast cancer patients. (E and F) are the relationship between expression level of CD8 in total level and DFS and OS of breast cancer patients.

Figure 3

The relationship between expression level of FoxP3 and DFS and OS of breast cancer patients. (A and B) are the relationship between expression level of FoxP3 in tumor nest and DFS and OS of breast cancer patients. (C and D) are the relationship between expression level of FoxP3 in tumor stroma and DFS and OS of breast cancer patients. (E and F) are the relationship between expression level of FoxP3 in total level and DFS and OS of breast cancer patients.

Figure 4

The relationship between the ratio of FoxP3⁺/CD8⁺ and DFS and OS of breast cancer patients. (A and B) are the relationship between the ratio of FoxP3⁺/CD8⁺ in tumor nest and DFS and OS of breast cancer patients. (C and D) are the relationship between the ratio of FoxP3⁺/CD8⁺ in tumor stroma and DFS and OS of breast cancer patients. (E and F) are the relationship between the ratio of FoxP3⁺/CD8⁺ in total level and DFS and OS of breast cancer patients.