Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma
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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.961933/full |
| _version_ | 1818537502731927552 |
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| author | Yu Zeng Yonghua Cai Peng Chai Yangqi Mao Yanwen Chen Li Wang Kunlin Zeng Ziling Zhan Yuxin Xie Cuiying Li Hongchao Zhan Liqian Zhao Xiaoxia Chen Xiaoxia Zhu Yu Liu Ming Chen Ye Song Ye Song Aidong Zhou Aidong Zhou Aidong Zhou |
| author_facet | Yu Zeng Yonghua Cai Peng Chai Yangqi Mao Yanwen Chen Li Wang Kunlin Zeng Ziling Zhan Yuxin Xie Cuiying Li Hongchao Zhan Liqian Zhao Xiaoxia Chen Xiaoxia Zhu Yu Liu Ming Chen Ye Song Ye Song Aidong Zhou Aidong Zhou Aidong Zhou |
| author_sort | Yu Zeng |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T18:51:34Z |
| format | Article |
| id | doaj.art-956d75aea56f4d83b9b29ce90fd37a65 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T18:51:34Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-956d75aea56f4d83b9b29ce90fd37a652022-12-22T00:54:16ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-08-011310.3389/fimmu.2022.961933961933Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in gliomaYu Zeng0Yonghua Cai1Peng Chai2Yangqi Mao3Yanwen Chen4Li Wang5Kunlin Zeng6Ziling Zhan7Yuxin Xie8Cuiying Li9Hongchao Zhan10Liqian Zhao11Xiaoxia Chen12Xiaoxia Zhu13Yu Liu14Ming Chen15Ye Song16Ye Song17Aidong Zhou18Aidong Zhou19Aidong Zhou20Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, ChinaDepartment of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaDepartment of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaDepartment of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaDepartment of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, ChinaDepartment of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, ChinaDepartment of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, ChinaDepartment of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, ChinaDepartment of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, ChinaDepartment of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, ChinaDepartment of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, ChinaDepartment of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaDepartment of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, ChinaDepartment of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, ChinaDepartment of Neurosurgery, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Neurosurgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaDepartment of Neurosurgery, Ganzhou People’s Hospital, Ganzhou, ChinaDepartment of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, ChinaDepartment of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, ChinaGuangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, ChinaBackgroundPyroptosis 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.https://www.frontiersin.org/articles/10.3389/fimmu.2022.961933/fullgliomapyroptosisprognosistumor-associated microenvironmentimmunotherapysmall molecular inhibitor |
| spellingShingle | Yu Zeng Yonghua Cai Peng Chai Yangqi Mao Yanwen Chen Li Wang Kunlin Zeng Ziling Zhan Yuxin Xie Cuiying Li Hongchao Zhan Liqian Zhao Xiaoxia Chen Xiaoxia Zhu Yu Liu Ming Chen Ye Song Ye Song Aidong Zhou Aidong Zhou Aidong Zhou Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma Frontiers in Immunology glioma pyroptosis prognosis tumor-associated microenvironment immunotherapy small molecular inhibitor |
| title | Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma |
| title_full | Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma |
| title_fullStr | Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma |
| title_full_unstemmed | Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma |
| title_short | Optimization of cancer immunotherapy through pyroptosis: A pyroptosis-related signature predicts survival benefit and potential synergy for immunotherapy in glioma |
| title_sort | optimization of cancer immunotherapy through pyroptosis a pyroptosis related signature predicts survival benefit and potential synergy for immunotherapy in glioma |
| topic | glioma pyroptosis prognosis tumor-associated microenvironment immunotherapy small molecular inhibitor |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.961933/full |
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