Kong Yang, Xue Zhiwei, Wang Haiying, Cui Guangqiang, Chen Anjing, Liu Jie, Wang Jian, Li Xingang, Huang Bin
Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China.
Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, China.
Front Genet. 2022 Jul 5;13:890174. doi: 10.3389/fgene.2022.890174. eCollection 2022.
Rigorous molecular analysis of the immune cell environment and immune response of human tumors has led to immune checkpoint inhibitors as one of the most promising strategies for the treatment of human cancer. However, in human glioblastoma multiforme (GBM) which develops in part by attracting immune cell types intrinsic to the human brain (microglia), standard immunotherapy has yielded inconsistent results in experimental models and patients. Here, we analyzed publicly available expression datasets to identify molecules possibly associated with immune response originating from or influencing the tumor microenvironment in primary tumor samples. Using three glioma datasets (GSE16011, Rembrandt-glioma and TCGA-glioma), we first analyzed the data to distinguish between GBMs of high and low tumor cell purity, a reflection of the cellular composition of the tumor microenvironment, and second, to identify differentially expressed genes (DEGs) between these two groups using GSEA and other analyses. Tumor purity was negatively correlated with patient prognosis. The interferon gamma-related gene emerged as a DEG that was highly expressed in GBM and negatively correlated with tumor purity. tumors also tended to harbor mutations (31 vs. 9%, versus ) while tumors more often had sustained mutations (8 versus 36%, versus ). Prognosis of patients with tumors was also poor relative to patients with tumors. Further molecular in silico analysis demonstrated that high expression of was negatively correlated with CD8 T cells but positively correlated with macrophages with an M2 phenotype. Further functional analysis demonstrated that BST2 was associated with multiple immune checkpoints and cytokines, and may promote tumorigenesis and progression through interferon gamma, IL6/JAK/STAT3 signaling, IL2/STAT5 signaling and the TNF-α signaling NF-kB pathway. Finally, a series of experiments confirmed that the expression of BST2 can be significantly increased by IFN induction, and knockdown of BST2 can significantly inhibit the growth and invasion of GBM cells, and may affect the phenotype of tumor-associated macrophages. In conclusion, BST2 may promote the progression of GBM and may be a target for treatment.
对人类肿瘤的免疫细胞环境和免疫反应进行的严格分子分析，已使免疫检查点抑制剂成为治疗人类癌症最有前景的策略之一。然而，在部分通过吸引人类大脑固有的免疫细胞类型（小胶质细胞）而发生的多形性胶质母细胞瘤（GBM）中，标准免疫疗法在实验模型和患者中产生的结果并不一致。在此，我们分析了公开可用的表达数据集，以识别可能与原发性肿瘤样本中源自肿瘤微环境或影响肿瘤微环境的免疫反应相关的分子。使用三个胶质瘤数据集（GSE16011、Rembrandt - 胶质瘤和TCGA - 胶质瘤），我们首先分析数据以区分肿瘤细胞纯度高和低的GBM，这反映了肿瘤微环境的细胞组成，其次，使用GSEA和其他分析方法识别这两组之间的差异表达基因（DEG）。肿瘤纯度与患者预后呈负相关。干扰素γ相关基因作为一个DEG出现，其在GBM中高表达且与肿瘤纯度呈负相关。 肿瘤也倾向于携带 突变（31%对9%， 对 ），而 肿瘤更常发生持续性 突变（8%对36%， 对 ）。相对于 肿瘤患者， 肿瘤患者的预后也较差。进一步的计算机分子分析表明， 的高表达与CD8 T细胞呈负相关，但与具有M2表型的巨噬细胞呈正相关。进一步的功能分析表明，BST2与多个免疫检查点和细胞因子相关，并且可能通过干扰素γ、IL6/JAK/STAT3信号通路、IL2/STAT5信号通路和TNF - α信号 - NF - kB途径促进肿瘤发生和进展。最后，一系列实验证实，IFN诱导可显著增加BST2的表达，敲低BST2可显著抑制GBM细胞的生长和侵袭，并可能影响肿瘤相关巨噬细胞的表型。总之，BST2可能促进GBM的进展，并且可能是一个治疗靶点。
