B7-H3 on circulating epithelial tumor cells correlates with the proliferation marker, Ki-67, and may be associated with the aggressiveness of tumors in breast cancer patients

Abstract

Circulating epithelial tumor cells (CETCs) in peripheral blood are a prerequisite for the development of metastases. B7-H3 is an important immune checkpoint member of the B7 family and inhibits T-cell mediated antitumor immunity. Its expression is associated with a negative prognosis and a poor clinical outcome. Based on the clinical success of inhibitory immune checkpoint blockade, monoclonal antibodies (mAbs) against B7-H3 appear to be a promising therapeutic strategy. The proliferation biomarker, Ki-67, is used as a prognostic factor for breast cancer and reflects the proliferative potential of the tumor. In order to better understand the role of B7-H3 and Ki-67 in cancer development, in this study, we used a real-time biopsy for determining both biomarkers on CETCs in breast cancer patients. Blood from 50 patients suffering from breast cancer was analyzed for CETCs and the expression of B7-H3 and Ki-67 using the maintrac® method. B7-H3 expression on CETCs was found in 82% of the patients. The frequency of B7-H3- and Ki-67‑positive CETCs was significantly higher in patients who had received radiation therapy compared to patients who had not received irradiation. B7-H3‑positive CETCs seemed to be more aggressive as the percentage of B7-H3‑positive CETCs correlated with the percentage of cells positive for the proliferation marker, Ki-67 (r=0.72 P<0.001). A significant association between the Ki-67 and B7-H3 expression level on the CETCs and nodal status was observed. On the whole, the findings of this study indicate that breast cancer patients have detectable CETCs with a high frequency of B7-H3 expression regardless of the stage of the disease. B7-H3 seems to be an important factor in immune evasion and may thus be a promising target for anticancer therapies. Radiation may lead to an upregulation of B7-H3 expression on CETCs, which could be a possible mechanism of acquired radio-resistance.

B7-H3 regulates KIF15-activated ERK1/2 pathway and contributes to radioresistance in colorectal cancer

“…However, radioresistance, resulting in tumor recurrence and a poor prognosis, is still a major reason for treatment failure 2 . Previous studies have indicated that B7-H3 regulates various tumor biological processes, including radioresistance 14,25 . Consistent with these findings, we found that the B7-H3 mRNA and protein expression levels were significantly increased in CRC cells after X-ray irradiation.…”

“…immunologic and nonimmunologic functions of B7-H3 in tumors 7,10,14,25 , it will be valuable to develop blocking antibodies against B7-H3 for tumor therapy. 8H9, which targets B7-H3, combined with craniospinal irradiation has been determined to prolong the survival of patients with metastatic central nervous system neuroblastoma 29 .…”

“…Many studies have suggested that the aberrant expression of B7-H3 exists in different cancer types, including pancreatic carcinoma 8 , esophageal carcinoma 9 , hepatocellular cancer 10 , colorectal cancer 11 , non-small cell lung cancer 12 and gastric cancer 13 . The frequency of B7-H3-positive circulating epithelial tumor cells (CETCs) is significantly higher in breast cancer patients who receive radiotherapy than in patients who do not receive irradiation, suggesting that the upregulation of B7-H3 expression on CETCs could be a possible mechanism of acquired radioresistance in breast cancer patients 14 . Nevertheless, the functional roles and underlying signaling cascades of B7-H3 associated with radioresistance in CRC have yet to be investigated.…”

Upregulation of microRNA‑520a‑3p inhibits the proliferation, migration and invasion via spindle and kinetochore associated 2 in gastric cancer

“…2B). Recent studies have demonstrated that Ki-67 is closely associated with cell proliferation (20,21). Investigating the levels of Ki-67 showed that miR-520a-3p mimics significantly decreased Ki-67 expression in GC cells (P<0.01; Fig.…”

Immuno-Oncology Biomarkers for Personalized Immunotherapy in Breast Cancer

“…The expression of another important immune checkpoint member, B7-H3, on CTCs of breast cancer patients has been also reported. The B7-H3 positive CTCs showed pronounced correlation with Ki-67 expression, a tumor proliferation marker, and were proposed to be a potential biomarker or target for immune checkpoint blockade therapies in breast cancer (Pizon et al, 2018). CTCs are valuable source of tumor information to develop new biomarkers, however, there are some challenges on the reproducibility of the results which are linked to the applying various techniques for isolation and enriching of these cells.…”