与免疫原性细胞死亡相关的分类可预测低级别胶质瘤的预后、免疫微环境特征和对免疫治疗的反应。
Classification related to immunogenic cell death predicts prognosis, immune microenvironment characteristics, and response to immunotherapy in lower-grade gliomas.
机构信息
Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Hengyang Medical School, University of South China, Hengyang, Hunan, China.
出版信息
Front Immunol. 2023 Apr 19;14:1102094. doi: 10.3389/fimmu.2023.1102094. eCollection 2023.
BACKGROUND
Immunogenic cell death (ICD) is a form of cell death that elicits immune responses against the antigens found in dead or dying tumor cells. Growing evidence implies that ICD plays a significant role in triggering antitumor immunity. The prognosis for glioma remains poor despite many biomarkers being reported, and identifying ICD-related biomarkers is imminent for better-personalized management in patients with lower-grade glioma (LGG).
MATERIALS AND METHODS
We identified ICD-related differentially expressed genes (DEGs) by comparing gene expression profiles obtained across Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) cohorts. On the foundation of ICD-related DEGs, two ICD-related clusters were identified through consensus clustering. Then, survival analysis, functional enrichment analysis, somatic mutation analysis, and immune characteristics analysis were performed in the two ICD-related subtypes. Additionally, we developed and validated a risk assessment signature for LGG patients. Finally, we selected one gene (EIF2AK3) from the above risk model for experimental validation.
RESULTS
32 ICD-related DEGs were screened, dividing the LGG samples from the TCGA database into two distinct subtypes. The ICD-high subgroup showed worse overall survival (OS), greater immune infiltration, more active immune response process, and higher expression levels of HLA genes than the ICD-low subgroup. Additionally, nine ICD-related DEGs were identified to build the prognostic signature, which was highly correlated with the tumor-immune microenvironment and could unambiguously be taken as an independent prognostic factor and further verified in an external dataset. The experimental results indicated that EIF2AK3 expression was higher in tumors than paracancerous tissues, and high-expression EIF2AK3 was enriched in WHO III and IV gliomas by qPCR and IHC, and Knockdown of EIF2AK3 suppressed cell viability and mobility in glioma cells.
CONCLUSION
We established novel ICD-related subtypes and risk signature for LGG, which may be beneficial to improving clinical outcome prediction and guiding individualized immunotherapy.
背景
免疫原性细胞死亡（ICD）是一种细胞死亡形式，可引发针对死或垂死肿瘤细胞中抗原的免疫反应。越来越多的证据表明，ICD 在触发抗肿瘤免疫中起着重要作用。尽管已经报道了许多生物标志物，但胶质瘤的预后仍然很差，因此确定与 ICD 相关的生物标志物对于改善低级别胶质瘤（LGG）患者的个体化管理至关重要。
材料和方法
我们通过比较 GTEx 和 TCGA 队列中获得的基因表达谱，鉴定了与 ICD 相关的差异表达基因（DEGs）。在与 ICD 相关的 DEGs 的基础上，通过共识聚类确定了两个与 ICD 相关的聚类。然后，对两个与 ICD 相关的亚型进行生存分析、功能富集分析、体细胞突变分析和免疫特征分析。此外，我们为 LGG 患者开发并验证了一个风险评估模型。最后，我们从上述风险模型中选择一个基因（EIF2AK3）进行实验验证。
结果
筛选出 32 个与 ICD 相关的 DEGs，将 TCGA 数据库中的 LGG 样本分为两个不同的亚型。ICD-高亚组的总生存期（OS）更差，免疫浸润更多，免疫反应过程更活跃，HLA 基因的表达水平更高。此外，确定了 9 个与 ICD 相关的 DEGs 来构建预后模型，该模型与肿瘤免疫微环境高度相关，可明确作为独立的预后因素，并在外部数据集进一步验证。实验结果表明，EIF2AK3 在肿瘤中的表达高于癌旁组织，qPCR 和 IHC 显示高表达 EIF2AK3 富集于 WHO III 和 IV 级胶质瘤，敲低 EIF2AK3 可抑制胶质瘤细胞的活力和迁移。
结论
我们建立了新的与 ICD 相关的 LGG 亚型和风险模型，这可能有助于改善临床结局预测和指导个体化免疫治疗。
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