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

Abstract

BackgroundPyroptosis 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.MethodsThe 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.ResultsPatients 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.ConclusionThe 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.

The PANoptosis-related signature indicates the prognosis and tumor immune infiltration features of gliomas

“…We compared our model with several other prognostic models to assess the importance of the PANoptotic score for predicting the prognosis of glioma. The results showed that the prediction accuracy of our model was better than other models that have been reported (Chen et al, 2021;Liu P. et al 2022;Zeng et al, 2022) (Figures 5D-F and Supplementary Figures S5A-F).…”

“…In previous studies, transcriptomics-based prognostic models for glioma have also been proposed. For example, Chen et al constructed a prognostic model of glioblastoma based on the function of STEAP (Six-transmembrane epithelial antigen of the prostate) family, STEAP2-and STEAP3-based prognostic risk score ( Chen et al, 2021 ); Zeng et al researched a prognostic model of glioma based on pyroptosis named pyroptosis-related risk signature (PRRS) ( Zeng et al, 2022 ); Liu P. et al (2022) proposed a prognostic model of glioma based on m6A regulators model called risk score, etc. The predictive performance of our constructed model was better than each of the above models by comparison of area under the ROC curve (AUC).…”

AKR1B1 Represses Glioma Cell Proliferation through p38 MAPK-Mediated Bcl-2/BAX/Caspase-3 Apoptotic Signaling Pathways

“…Targeting Bcl-2 and/or activating BAX to restore caspase-3 activity may be a potential therapeutic strategy for glioma [ 26 , 27 ]. Several strategies, such as small molecule inhibitors, gene therapy, and immunotherapy, have been explored to modulate BAX and Bcl-2 expression and restore caspase-3 activity in glioma cells, with promising results in preclinical studies [ 28 , 29 , 30 ].…”