Abstract
Background: B7-H3 promotes tumor immune escape and is highly expressed in tumor tissues. Stromal cells in tumors, including fibroblasts, play an important role in this process; however, the role of B7-H3 in tumor fibroblasts has not been fully clarified.Methods: We examined B7-H3, CD31, and alpha-smooth muscle actin (α-SMA) protein expression in 268 gastric adenocarcinomas (GACs) by immunohistochemistry. The coexpression of B7-H3 with CD31 or α-SMA was examined using immunofluorescence double staining. Cytokine expression from fibroblasts treated with B7-H3 small interfering RNA (siRNA) was analyzed by a Quantitative reverse transcription-polymerase chain reaction (qPCR) and Enzyme-linked immunosorbent assay (ELISA). The transwell tests were conducted to assess the migration and invasion ability of fibroblasts. The overall survival was analyzed by a Kaplan-Meier analysis. Associations between categorical variables were assessed using the Pearson's Chi-square test or Fisher's exact test.Results: GAC patients with B7-H3 expression showed significantly poorer survival (P = 0.012). The overall survival of the group with high B7-H3 expression was significantly worse than the group with low B7-H3 expression in both tumor cells and in stromal cells (P = 0.007 and P = 0.048, respectively). B7-H3 expression correlated with many clinicopathological data, including tumor stage, tumor depth, lymph node involvement, and survival. Immunofluorescence staining showed that B7-H3 was expressed in tumor cells and α-SMA-positive fibroblasts. Remarkably, high expression of α-SMA was associated with a poor prognosis (P = 0.007), and the prognoses of patients with high stromal expression of B7-H3 and α-SMA were significantly worse than that of other combination types (P = 0.001). Additionally, the absence of B7-H3 led to decreased secretion of cytokines, such as interleukin (IL)-6 and vascular endothelial growth factor (VEGF), as well as a decline in migration and invasion ability in cancer-associated fibroblasts (CAFs).Conclusions: Patients with high B7-H3 expression either in tumor cells or in stromal cells had significantly poorer overall survival. Stromal B7-H3 expression was mostly detected in α-SMA-positive CAFs. GAC patients with both stromal B7-H3-high and α-SMA-high expression had significantly poorer overall survival, suggesting that stromal B7-H3 and α-SMA expression status can serve as an indicator of poor prognosis for GAC patients.
Highlights
A gastric adenocarcinoma (GAC) is a malignant tumor that originates from the gastric epithelium [1]
The initial success of the immune checkpoint programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade with monoclonal antibodies has led to more extensive research of other negative costimulatory molecules [7]; B7-H3 is an important immune checkpoint member of the B7 and CD28 families, and it is expressed in a wide range of cells including tumor cells, endothelial cells, natural killer cells, B cells, activated macrophages, dendritic cells, monocytes, and fibroblasts [8,9,10,11,12]
We examined 268 tumors taken from patients diagnosed with GAC using immunohistochemistry and tissue microarray (TMA)
Summary
A gastric adenocarcinoma (GAC) is a malignant tumor that originates from the gastric epithelium [1]. Immune checkpoint blockades with monoclonal antibodies against negative costimulatory molecules in tumors have attracted much attention. Cytotoxic Tlymphocyte-associated antigen 4 (CTLA-4) [3, 4], programmed death 1 (PD-1) [5], and programmed death-ligand 1 (PD-L1) [6] have achieved satisfactory therapeutic results in different cancer treatments. The initial success of the immune checkpoint PD-1/PD-L1 blockade with monoclonal antibodies has led to more extensive research of other negative costimulatory molecules [7]; B7-H3 is an important immune checkpoint member of the B7 and CD28 families, and it is expressed in a wide range of cells including tumor cells, endothelial cells, natural killer cells, B cells, activated macrophages, dendritic cells, monocytes, and fibroblasts [8,9,10,11,12]. Stromal cells in tumors, including fibroblasts, play an important role in this process; the role of B7-H3 in tumor fibroblasts has not been fully clarified
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