Tumor-infiltrating Lymphocytes, Tumor Characteristics, and Recurrence in Patients With Early Breast Cancer

Abstract

Background: The balance in the immune system between immune surveillance against non-self-antigens and tolerance of self-antigens is known to be associated with the prognosis of breast cancer patients. However, immunologic signals in tumor microenvironment according to biological characteristics of cancer cells have not been clearly elucidated. CD4(+) T cells, CD8(+) T cells, and forkhead box P3-positive (Foxp3(+)) regulatory T cells (Tregs) are the main keys for immune surveillance and tolerance, respectively. We evaluated the correlations between the immunologic balance and tumor characteristics and their impact on recurrence. Patients and Methods: CD8(+) T cells and Foxp3(+) Tregs were detected by immunohistochemistry using the paraffin-embedded tumor samples from the 72 patients with early stage (I to III) breast cancer. Clinicopathologic data including tumor size and grade, lymph node metastasis, stage, patient's age, expression status of estrogen receptor (ER), progesterone receptor, p53, Ki-67, and human epidermal growth factor receptor-2/neu, and recurrence were reviewed. Results: The decreased number of CD8(+) T cells was significantly associated with tumors with lymph node metastasis (P = 0.027), higher stage (stage III, P = 0.013), and immunopositivity of Ki-67 (P = 0.026). In contrast, the increased number of Foxp3(+) Tregs was significantly correlated with tumors with lymph node metastasis (P = 0.027), immunopositivity for p53 (P = 0.026), and positive for Ki-67 (P < 0.001). There were significant correlations between the increased Foxp3(+) Treg/CD4(+) T-cell ratio and lymph node metastasis (P = 0.011), the expression of ER (P = 0.023), and immunopositivity of p53 (P = 0.031) and Ki-67 (P = 0.003). Of note, lower Foxp3(+) Treg/CD4(+) T-cell ratio was significantly associated with triple-negative breast cancer (P = 0.004). Disease-free survival of analyzed patients was significantly associated with the number of Foxp3(+) Tregs (dichotomized by a cutoff point of 17, P = 0.014) only. Univariate analysis indicated that tumor grade (P = 0.017), the expression of ER (P = 0.032), and non-triple-negative breast cancer (P = 0.022) were independent prognostic factors for disease-free survival. Conclusions: Our data showed that lymph node metastases, immunopositivity of p53 and Ki67, and non-triple-negative tumors were associated with high regulatory T-cell infiltration. The role of immunologic balance as a prognostic marker for recurrence must be evaluated more clearly in the future study.