Expression of B7-H3, a Potential Factor of Tumor Immune Evasion in Combination with the Number of Regulatory T Cells, Affects Against Recurrence-Free Survival in Breast Cancer Patients

Abstract

BackgroundIn the tumor microenvironment, factors inhibiting the targeting of cancer cells by activated T cells have recently been noted. B7-H3 belongs to the B7 superfamily of immune regulatory ligands and plays an important role in the adaptive immune response of co-inhibitory/stimulatory factors in regulating T cells. However, the degree to which B7-H3 directly affects tumor immune evasion mechanisms remains unclear, particularly in patients with breast cancer. Regulatory T cells (Tregs) are known as a key player in the inhibition of immune mechanisms. The present study demonstrated that expression of B7-H3 on tumor cells and the number of Tregs in the tumor microenvironment independently affected prognosis in breast cancer patients.MethodsWe immunohistochemically investigated the presence of B7-H3 and forkhead box P3 (Foxp3)-positive Tregs in pathological specimens from 90 patients with breast cancer.ResultsPositive B7-H3 expression was associated with shorter recurrence-free survival (RFS) (p = 0.014). A higher percentage of Foxp3-positive cells also correlated with shorter RFS (p = 0.039). Multivariate analysis showed B7-H3 as an independent factor on RFS. Foxp3 expression in tumor-infiltrating lymphocytes (TILs) correlated significantly with larger tumor size (>2 cm), expression of human epidermal growth factor receptor 2 (HER2), and higher nuclear grade (p = 0.003, p < 0.001, p = 0.001, respectively). No correlation was identified between expression of B7-H3 and the percentage of Foxp3-positive TILs.ConclusionsB7-H3 and Foxp3 can be regarded as markers of poor prognosis in breast cancer. These expressions were not correlated, suggesting that B7-H3 expression plays an independent role in tumor immune evasion, regardless of Tregs.

Breast Cancer Detection by B7-H3–Targeted Ultrasound Molecular Imaging

“…For example, in human gastric adenocarcinomas, B7-H3 expression was associated with prolonged patient survival compared to receptor negative tumors (50). In contrast, recent studies showed that B7-H3 tumor expression may be a predictor of poor prognosis and increased risk for metastasis in other cancers such as renal, colon, breast, and ovarian cancers (37, 41, 43, 46). In women with breast cancer, tumor expression of B7-H3 was suggested as a predictor of early regional lymph node metastases (47, 51), advanced stage disease (51), and overall worsened prognosis (43).…”

Worse outcome in breast cancer with higher tumor-infiltrating FOXP3+ Tregs : a systematic review and meta-analysis

“…Several studies revealed that FOXP3+ TILs level had a negative impact on the prognosis of breast cancer [14, 31, 32]. However, the exact prognostic significance was still unclear and the information was limited.…”

Immunoregulatory Protein B7-H3 Reprograms Glucose Metabolism in Cancer Cells by ROS-Mediated Stabilization of HIF1α

“…Tumor infiltration with Tregs (Foxp3+ T cells) is associated with suppression of antitumor immunity and has been associated with worse prognosis in cancer patients (41,42). Interestingly, a recent study of breast cancer patients revealed that B7-H3 high/Foxp3 high tumor staining was associated with significantly shorter recurrence-free survival than that of B7-H3 low/Foxp3 low (43). Future studies should investigate whether B7-H3-induced metabolic reprogramming also plays a role in regulation of cancer immunity to favor tumor growth and metastasis.…”