J Breast Cancer.  2014 Mar;17(1):8-17.

Zonal Difference and Prognostic Significance of Foxp3 Regulatory T Cell Infiltration in Breast Cancer

• Kim S
• Lee A
• Lim W
• Park S
• Cho MS
• Koo H
• Moon BI
• Sung SH

Abstract

PURPOSE
Forkhead box P3 (Foxp3) is known as the most specific marker for regulatory T lymphocytes, which play an important role in immune tolerance to disturb antitumor immunity. The present study aimed to investigate the prognostic significance of Foxp3 regulatory T lymphocyte (Foxp3 Treg) infiltration in breast cancer.
METHODS
Immunohistochemical studies with Foxp3, CD4, and CD8 were performed on representative full tissue sections from 143 patients with invasive ductal carcinoma, not otherwise specified. Foxp3 Treg infiltration and the ratios between Foxp3 Treg and CD4 or CD8 T cells were separately analyzed for the tumor bed and tumor periphery to evaluate their association with different clinicopathological parameters and patients' outcome.
RESULTS
The tumor periphery was considerably more densely infiltrated by Foxp3 Treg, CD4, and CD8 T cells than the tumor bed. Unfavorable clinicopathological parameters (a Ki-67 labeling index of > or =14%, a worse histologic grade, a worse nuclear grade, hormone receptor negativity, human epidermal growth factor receptor 2 positivity, and tumor recurrence) were associated with increased Foxp3 Treg infiltration and a high ratio between Foxp3 Treg and CD4/CD8 T cells. In the tumor periphery, as Foxp3 Treg infiltration and the Foxp3 Treg/CD8 ratio increased, patients' 5-year disease-free survival rate decreased.
CONCLUSION
The infiltration densities of Foxp3 Treg, CD4, and CD8 T cells were markedly different between the tumor bed and periphery. Besides the absolute count of Foxp3 Treg, the ratio between Foxp3 Treg and effector T cells was a significant prognostic factor in breast cancer.

Keyword

Breast neoplasms; Foxp3 protein; Humans; T-lymphocyte; Regulatory

MeSH Terms

Breast Neoplasms*
Breast*
Carcinoma, Ductal
Disease-Free Survival
Fluconazole*
Humans
Immune Tolerance
Lymphocytes
Receptor, Epidermal Growth Factor
T-Lymphocytes
T-Lymphocytes, Regulatory
Fluconazole
Receptor, Epidermal Growth Factor

Figure

• 

  Figure 1 immunohistochemical (IHC) staining of CD4 in tumor periphery (IHC stain for CD4, ×200) (A), CD4 in tumor bed (IHC stain for CD4, ×200) (B), CD8 in tumor periphery (IHC stain for CD8, ×200) (C), CD8 in tuomr bed (IHC stain for CD8, ×200) (D), Foxp3 in tumor periphery (IHC stain for Foxp3, ×200) (E), and Foxp3 in tumor bed (IHC stain for Foxp3, ×200) (F). Tumor periphery shows denser infiltration of CD4, and CD8 T cells, and Foxp3 Tregs than tumor bed.

• 

  Figure 2 (A) Kaplan-Meier survival curve comparing the high and the low forkhead box P3 (Foxp3) T reg infiltration group in tumor periphery. The 5-year disease-free survival (DFS) rate was higher in low Foxp3 Treg group than in the high Foxp3 Treg group (p=0.042). (B) Kaplan-Meier survival curve comparing the high Foxp3 Treg/CD8 group and the low Foxp3 Treg/CD8 group in tumor periphery. The 5-year DFS rate was higher in the low Foxp3 Treg/CD8 T cell group than in the high Foxp3 Treg/CD8 T cell group (p=0.012).

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