New insights of CTLA-4 into its biological function in breast cancer.

CTLA-4 is a negative regulator of the proliferation and the effector function of T-cells. Therefore, it might be important to determine its expression on tumor cells and T-lymphocytes from cancer patients, to investigate its role in initiating and maintaining the neoplastic pathogenesis. CTLA-4 expression was detected in breast tissue by immunohistochemical staining and RT-PCR in 60 patients with breast cancer and 30 normal controls. The levels of CTLA-4 on T lymphocytes in 33 of the patients and 27 of the control group were determined by flow cytometry. Isolated peripheral blood mononuclear cells (PBMCs) were stimulated with phytohaemagglutinin (PHA). Stimulation index and IL-2 level in the cell culture supernatant were measured by MTT assay and ELISA method, respectively. Patients showed strong expression of CTLA-4 in the tumor cells of all specimens at both the protein and mRNA level, but only weakly positive or negative expression in normal breast tissue. Patients with higher mRNA level of CTLA-4 had obvious axillary lymph nodes metastases and higher clinical stage. Spontaneous expression of CD3 CTLA-4 on PBMCs of tumor patients was also significantly higher than that of the controls. Moreover, PBMCs derived from patients with high expression of CD3 CTLA-4 T-cells showed poor responsiveness to PHA stimulation and lower IL-2 production. Therefore, abnormal expression and dysregulation of CTLA-4 could partly explain the mechanism of evasion of anti-tumor immune responses in breast cancer patients and therefore highlight its importance in the development and progression of breast cancer.