Zhan Shenghua, Liu Zhiju, Zhang Min, Guo Tianwei, Quan Qiuying, Huang Lili, Guo Lingchuan, Cao Lei, Zhang Xueguang
Department of Pathology, Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Front Oncol. 2020 Jan 10;9:1466. doi: 10.3389/fonc.2019.01466. eCollection 2019.
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. 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. GAC patients with B7-H3 expression showed significantly poorer survival ( = 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 ( = 0.007 and = 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 ( = 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 ( = 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). 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.
B7-H3促进肿瘤免疫逃逸，且在肿瘤组织中高表达。肿瘤中的基质细胞，包括成纤维细胞，在此过程中起重要作用；然而，B7-H3在肿瘤成纤维细胞中的作用尚未完全阐明。我们通过免疫组织化学检测了268例胃腺癌（GAC）中B7-H3、CD31和α平滑肌肌动蛋白（α-SMA）的蛋白表达。使用免疫荧光双重染色检测B7-H3与CD31或α-SMA的共表达。通过定量逆转录聚合酶链反应（qPCR）和酶联免疫吸附测定（ELISA）分析用B7-H3小干扰RNA（siRNA）处理的成纤维细胞的细胞因子表达。进行Transwell试验以评估成纤维细胞的迁移和侵袭能力。通过Kaplan-Meier分析分析总生存期。使用Pearson卡方检验或Fisher精确检验评估分类变量之间的关联。B7-H3表达的GAC患者生存期明显较差（P = 0.012）。在肿瘤细胞和基质细胞中，B7-H3高表达组的总生存期均明显差于B7-H3低表达组（分别为P = 0.007和P = 0.048）。B7-H3表达与许多临床病理数据相关，包括肿瘤分期、肿瘤深度、淋巴结受累情况和生存期。免疫荧光染色显示B7-H3在肿瘤细胞和α-SMA阳性成纤维细胞中表达。值得注意的是，α-SMA高表达与预后不良相关（P = 0.007），B7-H3和α-SMA基质高表达患者的预后明显差于其他组合类型（P = 0.001）。此外，B7-H3的缺失导致细胞因子如白细胞介素（IL）-6和血管内皮生长因子（VEGF）的分泌减少，以及癌症相关成纤维细胞（CAF）的迁移和侵袭能力下降。肿瘤细胞或基质细胞中B7-H3高表达的患者总生存期明显较差。基质B7-H3表达大多在α-SMA阳性CAF中检测到。基质B7-H3高表达和α-SMA高表达的GAC患者总生存期明显较差，表明基质B7-H3和α-SMA表达状态可作为GAC患者预后不良的指标。
