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Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma

上睑下垂 免疫疗法 胶质瘤 基因签名 医学 免疫系统 癌症研究 队列 肿瘤科 生物 免疫学 内科学 基因表达 基因 炎症 生物化学 炎症体
作者
Yu Zeng,Yonghua Cai,Ping Chai,Yangqi Mao,Yanwen Chen,Li Wang,Kunlin Zeng,Ziling Zhan,Yuxin Xie,Cuiying Li,Hongchao Zhan,Lihua Zhao,Xiaoxia Chen,Xiaoli Zhu,Yu Liu,Ming Chen,Ye Song,Aidong Zhou
出处
期刊:Frontiers in Immunology [Frontiers Media SA]
卷期号:13 被引量:2
标识
DOI:10.3389/fimmu.2022.961933
摘要

Pyroptosis is a critical type of programmed cell death that is strongly associated with the regulation of tumor and immune cell functions. However, the role of pyroptosis in tumor progression and remodeling of the tumor microenvironment in gliomas has not been extensively studied. Thus, in this study, we aimed to establish a comprehensive pyroptosis-related signature and uncover its potential clinical application in gliomas.The TCGA glioma cohort was obtained and divided into training and internal validation cohorts, while the CGGA glioma cohort was used as an external validation cohort. Unsupervised consensus clustering was performed to identify pyroptosis-related expression patterns. A Cox regression analysis was performed to establish a pyroptosis-related risk signature. Real-time quantitative PCR was performed to analyze the expression of signature genes in glioma tissues. Immune infiltration was analyzed and validated by immunohistochemical staining. The expression patterns of signature genes in different cell types were analyzed using single-cell RNA sequencing data. Finally, therapeutic responses to chemotherapy, immunotherapy, and potential small-molecule inhibitors were investigated.Patients with glioma were stratified into clusters 1 and 2 based on the expression patterns of pyroptosis-related genes. Cluster 2 showed a longer overall (P<0.001) and progression-free survival time (P<0.001) than Cluster 1. CD8+ T cell enrichment was observed in Cluster 1. A pyroptosis-related risk signature (PRRS) was then established. The high PRRS group showed a significantly poorer prognosis than the low PRRS group in the training cohort (P<0.001), with validation in the internal and external validation cohorts. Immunohistochemical staining demonstrated that CD8+ T cells were enriched in high PRRS glioma tissues. PRRS genes also showed cell-specific expression in tumor and immune cells. Moreover, the high PRRS risk group showed higher temozolomide sensitivity and increased response to anti-PD1 treatment in a glioblastoma immunotherapy cohort. Finally, Bcl-2 inhibitors were screened as candidates for adjunct immunotherapy of gliomas.The pyroptosis-related signature established in this study can be used to reliably predict clinical outcomes and immunotherapy responses in glioma patients. The correlation between the pyroptosis signature and the tumor immune microenvironment may be used to further guide the sensitization of glioma patients to immunotherapy.
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