{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T12:35:37Z","timestamp":1776947737092,"version":"3.51.4"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T00:00:00Z","timestamp":1623801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005089","name":"Beijing Municipal Natural Science Foundation","doi-asserted-by":"publisher","award":["7202150, 19JCZDJC64200(Z)"],"award-info":[{"award-number":["7202150, 19JCZDJC64200(Z)"]}],"id":[{"id":"10.13039\/501100005089","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The immunosuppressive mechanisms of the surrounding microenvironment and distinct immunogenomic features in glioblastoma (GBM) have not been elucidated to date. To fill this gap, useful data were extracted from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), GSE16011, GSE43378, GSE23806, and GSE12907. With the ssGSEA method and the ESTIMATE and CIBERSORT algorithms, four microenvironmental signatures were used to identify glioma microenvironment genes, and the samples were reasonably classified into three immune phenotypes. The molecular and clinical features of these phenotypes were characterized <jats:italic>via<\/jats:italic> key gene set expression, tumor mutation burden, fraction of immune cell infiltration, and functional enrichment. Exhausted CD8+ T cell (GET) signature construction with the predictive response to commonly used antitumor drugs and peritumoral edema assisted in further characterizing the immune phenotype features. A total of 2,466 glioma samples with gene expression profiles were enrolled. Tumor purity, ESTIMATE, and immune and stromal scores served as the 4 microenvironment signatures used to classify gliomas into immune-high, immune-middle and immune-low groups, which had distinct immune heterogeneity and clinicopathological characteristics. The immune-H phenotype had higher expression of four immune signatures; however, most checkpoint molecules exhibited poor survival. Enriched pathways among the subtypes were related to immunity. The GET score was similar among the three phenotypes, while immune-L was more sensitive to bortezomib, cisplatin, docetaxel, lapatinib, and rapamycin prescriptions and displayed mild peritumor edema. The three novel immune phenotypes with distinct immunogenetic features could have utility for understanding glioma microenvironment regulation and determining prognosis. These results contribute to classifying glioma subtypes, remodeling the immunosuppressive microenvironment and informing novel cancer immunotherapy in the era of precision immuno-oncology.<\/jats:p>","DOI":"10.3389\/fimmu.2021.557994","type":"journal-article","created":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T09:50:09Z","timestamp":1623837009000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Investigation of Genetic Determinants of Glioma Immune Phenotype by Integrative Immunogenomic Scale Analysis"],"prefix":"10.3389","volume":"12","author":[{"given":"Binghao","family":"Zhao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuekun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaning","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Congxin","family":"Dai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenbin","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer Statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2016.01.024","article-title":"CGCG Clinical Practice Guidelines for the Management of Adult Diffuse Gliomas","volume":"375","author":"Jiang","year":"2016","journal-title":"Cancer Lett"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nature14432","article-title":"Structural and Functional Features of Central Nervous System Lymphatic Vessels","volume":"523","author":"Louveau","year":"2015","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.ccell.2017.07.006","article-title":"Macrophage Polarization Contributes to Glioblastoma Eradication by Combination Immunovirotherapy and Immune Checkpoint Blockade","volume":"32","author":"Saha","year":"2017","journal-title":"Cancer Cell"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e1328339","DOI":"10.1080\/2162402X.2017.1328339","article-title":"Molecular and Clinical Characterization of TIM-3 in Glioma Through 1,024 Samples","volume":"6","author":"Li","year":"2017","journal-title":"Oncoimmunology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgv033","article-title":"Chemical Compounds From Anthropogenic Environment and Immune Evasion Mechanisms: Potential Interactions","volume":"36","author":"Kravchenko","year":"2015","journal-title":"Carcinogenesis"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e1196310","DOI":"10.1080\/2162402X.2016.1196310","article-title":"Molecular and Clinical Characterization of PD-L1 Expression at Transcriptional Level Via 976 Samples of Brain Glioma","volume":"5","author":"Wang","year":"2016","journal-title":"Oncoimmunology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e1426516","DOI":"10.1080\/2162402X.2018.1426516","article-title":"Immune Heterogeneity and Clinicopathologic Characterization of IGFBP2 in 2447 Glioma Samples","volume":"7","author":"Cai","year":"2018","journal-title":"Oncoimmunology"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1407279","article-title":"Glioma Groups Based on 1p\/19q, IDH, and TERT Promoter Mutations in Tumors","volume":"372","author":"Eckel-Passow","year":"2015","journal-title":"N Engl J Med"},{"key":"B10","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.ccr.2009.12.020","article-title":"Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, Idh1, EGFR, and NF1","volume":"17","author":"Verhaak","year":"2010","journal-title":"Cancer Cell"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.01.067","article-title":"DNA Damage Repair Alterations Modulate M2 Polarization of Microglia to Remodel the Tumor Microenvironment Via the P53-Mediated MDK Expression in Glioma","volume":"41","author":"Meng","year":"2019","journal-title":"EBioMedicine"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-018-0003-5","article-title":"Current State of Immunotherapy for Glioblastoma","volume":"15","author":"Lim","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/nature07385","article-title":"Comprehensive Genomic Characterization Defines Human Glioblastoma Genes and Core Pathways","volume":"455","author":"McLendon","year":"2008","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.9.4772","article-title":"A Functional Role of HLA-G Expression in Human Gliomas: An Alternative Strategy of Immune Escape","volume":"168","author":"Wiendl","year":"2002","journal-title":"J Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3171\/jns.2002.96.3.0580","article-title":"Apoptosis of T Lymphocytes Invading Glioblastomas Multiforme: A Possible Tumor Defense Mechanism","volume":"96","author":"Didenko","year":"2002","journal-title":"J Neurosurg"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/nm1517","article-title":"Loss of Tumor Suppressor PTEN Function Increases B7-H1 Expression and Immunoresistance in Glioma","volume":"13","author":"Parsa","year":"2007","journal-title":"Nat Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2035","article-title":"T Cell Exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/nm1197","article-title":"Dendritic Cells Permit Immune Invasion of the CNS in an Animal Model of Multiple Sclerosis","volume":"11","author":"Greter","year":"2005","journal-title":"Nat Med"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2612","DOI":"10.1038\/ncomms3612","article-title":"Inferring Tumour Purity and Stromal and Immune Cell Admixture From Expression Data","volume":"4","author":"Yoshihara","year":"2013","journal-title":"Nat Commun"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1172\/JCI65833","article-title":"Prognostically Relevant Gene Signatures of High-Grade Serous Ovarian Carcinoma","volume":"123","author":"Verhaak","year":"2013","journal-title":"J Clin Invest"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1109\/TPAMI.2004.1261097","article-title":"Two-Dimensional PCA: A New Approach to Appearance-Based Face Representation and Recognition","volume":"26","author":"Yang","year":"2004","journal-title":"IEEE Trans Pattern Anal Mach intell"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1101\/gr.239244.118","article-title":"Maftools: Efficient and Comprehensive Analysis of Somatic Variants in Cancer","volume":"28","author":"Mayakonda","year":"2018","journal-title":"Genome Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3337","article-title":"Robust Enumeration of Cell Subsets From Tissue Expression Profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat Methods"},{"key":"B24","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1038\/s41591-018-0057-z","article-title":"A Transcriptionally and Functionally Distinct PD-1(+) Cd8(+) T Cell Pool With Predictive Potential in non-Small-Cell Lung Cancer Treated With PD-1 Blockade","volume":"24","author":"Thommen","year":"2018","journal-title":"Nat Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/path.5435","article-title":"T-Cell Exhaustion Interrelates With Immune Cytolytic Activity to Shape the Inflamed Tumor Microenvironment","volume":"251","author":"Cai","year":"2020","journal-title":"J pathol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102","article-title":"Gene Set Enrichment Analysis: A Knowledge-Based Approach for Interpreting Genome-Wide Expression Profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"B27","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1471-2105-14-7","article-title":"Gsva: Gene Set Variation Analysis for Microarray and RNA-Seq Data","volume":"14","author":"H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinf"},{"key":"B28","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1093\/bioinformatics\/btu393","article-title":"N Circlize\\N Implements and Enhances Circular Visualization in R\\N","volume":"19","author":"Gu","year":"2014","journal-title":"Bioinformatics"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1101\/gr.092759.109","article-title":"Circos: An Information Aesthetic for Comparative Genomics","volume":"19","author":"Krzywinski","year":"2009","journal-title":"Genome Res"},{"key":"B30","article-title":"Interactive Sankey Diagrams. Paper Presented at: IEEE Symposium on Information Visualization, 2005","volume":"2005","author":"Riehmann","year":"2005","journal-title":"INFOVIS 2005"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1111","article-title":"Genomics of Drug Sensitivity in Cancer (GDSC): A Resource for Therapeutic Biomarker Discovery in Cancer Cells","volume":"41","author":"Yang","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"B32","doi-asserted-by":"publisher","first-page":"R47","DOI":"10.1186\/gb-2014-15-3-r47","article-title":"Clinical Drug Response can be Predicted Using Baseline Gene Expression Levels and In Vitro Drug Sensitivity in Cell Lines","volume":"15","author":"Geeleher","year":"2014","journal-title":"Genome Biol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.06.017","article-title":"A Landscape of Pharmacogenomic Interactions in Cancer","volume":"166","author":"Iorio","year":"2016","journal-title":"Cell"},{"key":"B34","article-title":"MR Imaging Correlates of Survival in Patients With High-Grade Gliomas","volume":"26","author":"Pope","year":"2005","journal-title":"AJNR Am J neuroradiol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1586\/erm.09.44","article-title":"Genetic Signature of Adult Gliomas and Correlation With MRI Features","volume":"9","author":"Bruzzone","year":"2009","journal-title":"Expert Rev Mol diagn"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A2950","article-title":"Relationship Between Tumor Enhancement, Edema, IDH1 Mutational Status, MGMT Promoter Methylation, and Survival in Glioblastoma","volume":"33","author":"Carrillo","year":"2012","journal-title":"AJNR Am J neuroradiol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1016\/j.immuni.2018.03.023","article-title":"The Immune Landscape of Cancer","volume":"48","author":"Thorsson","year":"2018","journal-title":"Immunity"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2018.01.011","article-title":"A Comprehensive Immunologic Portrait of Triple-Negative Breast Cancer","volume":"11","author":"Liu","year":"2018","journal-title":"Trans Oncol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2018.07.012","article-title":"Immunogenomics Analysis Reveals That TP53 Mutations Inhibit Tumor Immunity in Gastric Cancer","volume":"11","author":"Jiang","year":"2018","journal-title":"Trans Oncol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2019.07.009","article-title":"Correlate the TP53 Mutation and the HRAS Mutation With Immune Signatures in Head and Neck Squamous Cell Cancer","volume":"17","author":"Lyu","year":"2019","journal-title":"Comput Struct Biotechnol J"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-18540-2","article-title":"Modeling Tumor Immunity of Mouse Glioblastoma by Exhausted CD8(+) T Cells","volume":"8","author":"Nakashima","year":"2018","journal-title":"Sci Rep"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.52176","article-title":"Understanding the Glioblastoma Immune Microenvironment as Basis for the Development of New Immunotherapeutic Strategies","volume":"9","author":"Pombo Antunes","year":"2020","journal-title":"eLife"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.11.003","article-title":"Il-10 Elicits IFNgamma-dependent Tumor Immune Surveillance","volume":"20","author":"Mumm","year":"2011","journal-title":"Cancer Cell"},{"key":"B44","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/nrclinonc.2016.217","article-title":"Tumour-Associated Macrophages as Treatment Targets in Oncology","volume":"14","author":"Mantovani","year":"2017","journal-title":"Nat Rev Clin Oncol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1643","DOI":"10.1016\/j.cell.2020.05.007","article-title":"Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells","volume":"181","author":"Klemm","year":"2020","journal-title":"Cell"},{"key":"B46","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.cell.2016.02.065","article-title":"Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma","volume":"165","author":"Hugo","year":"2016","journal-title":"Cell"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.20892\/j.issn.2095-3941.2019.0353","article-title":"Neutrophil Extracellular Traps Mediate the Crosstalk Between Glioma Progression and the Tumor Microenvironment Via the HMGB1\/RAGE\/IL-8 Axis","volume":"17","author":"Zha","year":"2020","journal-title":"Cancer Biol Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nop023","article-title":"Normal Human Monocytes Exposed to Glioma Cells Acquire Myeloid-Derived Suppressor Cell-Like Properties","volume":"12","author":"Rodrigues","year":"2010","journal-title":"Neuro-Oncology"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/nature11132","article-title":"Ppar-\u03b3 is a Major Driver of the Accumulation and Phenotype of Adipose Tissue T_(reg) Cells","volume":"486","author":"Cipolletta","year":"2012","journal-title":"Nature"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2871","article-title":"Bat3 Promotes T Cell Responses and Autoimmunity by Repressing Tim-3-mediated Cell Death and Exhaustion","volume":"18","author":"Rangachari","year":"2012","journal-title":"Nat Med"},{"key":"B51","doi-asserted-by":"publisher","first-page":"eaay0524","DOI":"10.1126\/science.aay0524","article-title":"VISTA is a Checkpoint Regulator for Na\u00efve T Cell Quiescence and Peripheral Tolerance","volume":"367","author":"ElTanbouly","year":"2020","journal-title":"Science"},{"key":"B52","doi-asserted-by":"publisher","first-page":"eaax0182","DOI":"10.1126\/science.aax0182","article-title":"Neoadjuvant Checkpoint Blockade for Cancer Immunotherapy","volume":"367","author":"Topalian","year":"2020","journal-title":"Science"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/nature19330","article-title":"Defining CD8+ T Cells That Provide the Proliferative Burst After PD-1 Therapy","volume":"537","author":"Im","year":"2016","journal-title":"Nature"},{"key":"B54","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1186\/s13059-016-1028-7","article-title":"Comprehensive Analyses of Tumor Immunity: Implications for Cancer Immunotherapy","volume":"17","author":"Li","year":"2016","journal-title":"Genome Biol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32102","article-title":"Immunogenomic Analysis Reveals LGALS1 Contributes to the Immune Heterogeneity and Immunosuppression in Glioma","volume":"145","author":"Chen","year":"2019","journal-title":"Int J Cancer"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.09.035","article-title":"A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization","volume":"175","author":"Sanmamed","year":"2018","journal-title":"Cell"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4415","article-title":"Targeting Glioma Stem Cells Through Combined BMI1 and EZH2 Inhibition","volume":"23","author":"Jin","year":"2017","journal-title":"Nat Med"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1713444","article-title":"Tumor Mutational Burden and Response Rate to PD-1 Inhibition","volume":"377","author":"Yarchoan","year":"2017","journal-title":"N Engl J Med"},{"key":"B59","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1038\/s41586-020-1969-6","article-title":"Pan-Cancer Analysis of Whole Genomes","volume":"578","author":"Campbell","year":"2020","journal-title":"Nature"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.557994\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T09:50:16Z","timestamp":1623837016000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.557994\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,16]]},"references-count":59,"alternative-id":["10.3389\/fimmu.2021.557994"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.557994","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,16]]},"article-number":"557994"}}