Department of Molecular Pathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Front Immunol. 2019 Aug 2;10:1756. doi: 10.3389/fimmu.2019.01756. eCollection 2019.
Immunotherapy provided unprecedented advances in the treatment of several previously untreated cancers. However, these immunomodulatory maneuvers showed limited response to patients with glioma in clinical trials. Our aim was to depict the immune characteristics of glioma with immune cytolytic activity at genetic and transcriptome levels. In total, 325 gliomas from CGGA dataset as training cohort and 699 gliomas from TCGA dataset as validation cohort were enrolled in our analysis. We calculated the immune cytolytic activity for 1,000 of gliomas. The characteristics of immune cytolytic activity in gliomas were interpreted by the corresponding clinical, molecular genetics and radiological information. We found that immune cytolytic activity was highly associated with molecular, clinical, and edema extent. High cytolytic activity gliomas were more likely to be diagnosed as glioblastoma and might be a potential marker of mesenchymal subtype. Moreover, those gliomas exhibited significantly increased copy number alterations including recurrent focal amplifications of PDGFA and EGFR, as well as recurrent deletions of CDKN2A/B. Subsequent biological function analysis revealed that the immune response and immune checkpoints expression were significantly correlated with the cytolytic activity of gliomas. Immune cytolytic activity was significantly positively associated with the extent of peri-tumor edema and was independently correlated with reduced survival time. Our results highlighted the immunoregulatory mechanism heterogeneity of gliomas. Cytolytic activity, indirectly reflected by the extent of peri-tumor edema, may provide a potential index to evaluate the status of immune microenvironment and immune checkpoints in glioma, which should be fully valued for precision classification and immunotherapy.
免疫疗法为几种以前未经治疗的癌症的治疗提供了前所未有的进展。然而，这些免疫调节手段在临床试验中对胶质母细胞瘤患者的反应有限。我们的目的是描绘具有免疫细胞溶解活性的胶质母细胞瘤的免疫特征，在基因和转录组水平上。
总共从 CGGA 数据集招募了 325 例胶质母细胞瘤作为训练队列，从 TCGA 数据集招募了 699 例胶质母细胞瘤作为验证队列。我们计算了 1000 例胶质母细胞瘤的免疫细胞溶解活性。通过相应的临床、分子遗传学和影像学信息来解释胶质母细胞瘤中免疫细胞溶解活性的特征。
我们发现免疫细胞溶解活性与分子、临床和水肿程度高度相关。高细胞溶解活性的胶质母细胞瘤更可能被诊断为胶质母细胞瘤，并且可能是间充质亚型的潜在标志物。此外，这些胶质母细胞瘤表现出明显增加的拷贝数改变，包括 PDGFA 和 EGFR 的反复局灶性扩增，以及 CDKN2A/B 的反复缺失。随后的生物学功能分析表明，免疫反应和免疫检查点表达与胶质母细胞瘤的细胞溶解活性显著相关。免疫细胞溶解活性与肿瘤周围水肿的程度呈显著正相关，与生存时间的缩短独立相关。
我们的结果强调了胶质母细胞瘤免疫调节机制的异质性。细胞溶解活性，间接反映为肿瘤周围水肿的程度，可能为评估免疫微环境和免疫检查点在胶质母细胞瘤中的状态提供一个潜在的指标，应该充分重视其用于精准分类和免疫治疗。
