Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, China.
Department of Neurosurgery and Medical Rehabilitation ICPE, Bashkir State Medical University, Ufa, Russia.
Int J Cancer. 2019 Jul 15;145(2):517-530. doi: 10.1002/ijc.32102. Epub 2019 Jan 22.
Mutualistic and dynamic communication between tumour cells and the surrounding microenvironment accelerates the initiation, progression, chemoresistance and immune evasion of glioblastoma (GBM). However, the immunosuppressive mechanisms of GBM has not been thoroughly elucidated to date. We enrolled six microenvironmental signatures to identify glioma microenvironmental genes. The functional enrichment analysis such as ssGSEA, ESTIMATE algorithm, Gene Ontology, Pathway analysis is conducted to discover the potential function of microenvironmental genes. In vivo and in vitro experiments are used to verify the immunologic function of LGALS1 in GBM. We screen eight glioma microenvironmental genes from glioma databases, and discover a key immunosuppressive gene (LGALS1 encoding Galectin-1) exhibiting obviously prognostic significance among glioma microenvironmental genes. Gliomas with different LGALS1 expression have specific genomic variation spectrums. Immunosuppression is a predominate characteristic in GBMs with high expression of LGALS1. Knockdown of LGALS1 remodels the GBM immunosuppressive microenvironment by down regulating M2 macrophages and myeloid-derived suppressor cells (MDSCs), and inhibiting immunosuppressive cytokines. Our results thus implied an important role of microenvironmental regulation in glioma malignancy and provided evidences of LGALS1 contributing to immunosuppressive environment in glioma and that targeting LGALS1 could remodel immunosuppressive microenvironment of glioma.
肿瘤细胞与周围微环境之间的互利和动态交流加速了胶质母细胞瘤（GBM）的发生、进展、化疗耐药和免疫逃逸。然而，迄今为止，GBM 的免疫抑制机制尚未得到彻底阐明。我们招募了六个微环境特征来鉴定神经胶质瘤微环境基因。通过 ssGSEA、ESTIMATE 算法、基因本体论、通路分析等功能富集分析，发现微环境基因的潜在功能。通过体内和体外实验验证 LGALS1 在 GBM 中的免疫功能。我们从神经胶质瘤数据库中筛选出 8 个神经胶质瘤微环境基因，并发现一个关键的免疫抑制基因（LGALS1 编码半乳糖凝集素-1）在神经胶质瘤微环境基因中表现出明显的预后意义。具有不同 LGALS1 表达的神经胶质瘤具有特定的基因组变异谱。在 LGALS1 高表达的 GBM 中，免疫抑制是一个主要特征。LGALS1 的敲低通过下调 M2 巨噬细胞和髓系来源的抑制细胞（MDSCs）以及抑制免疫抑制细胞因子来重塑 GBM 的免疫抑制微环境。因此，我们的结果表明微环境调节在神经胶质瘤恶性程度中起着重要作用，并提供了 LGALS1 有助于神经胶质瘤免疫抑制环境的证据，以及靶向 LGALS1 可以重塑神经胶质瘤的免疫抑制微环境。
