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pmid:34220791
Investigation of Genetic Determinants of Glioma Immune Phenotype by Integrative Immunogenomic Scale Analysis.
Binghao Zhao · Yuekun Wang · Yaning Wang · Congxin Dai · Yu Wang · Wenbin Ma
Frontiers in immunology · 2021 doi:10.3389/fimmu.2021.557994
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Complete file
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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 via 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. 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["GBM (%)", "86 (21.1)", "GBM (%)", "161 (40.1)", "GBM (%)", "110 (64.3)"], ["CGGA microarray cohort", "IDH Status", "IDH MT(%)", "62 (59.6)", "IDH MT(%)", "47 (52.2)", "IDH MT(%)", "25 (23.8)", "χ2 = 29.941; P < 0.001"], ["IDH WT (%)", "42 (40.4)", "IDH WT (%)", "43 (47.8)", "IDH WT (%)", "80 (76.2)"], ["Glioma Type", "Primary (%)", "92 (91.1)", "Primary (%)", "83 (95.4)", "Primary (%)", "88 (88.9)", "χ2 = 2.625; P = 0.269"], ["Recurrent (%)", "9 (8.9)", "Recurrent (%)", "4 (4.6)", "Recurrent (%)", "11 (11.1)"], ["Glioma Grade", "LGG (%)", "82 (78.1)", "LGG (%)", "53 (58.9)", "LGG (%)", "39 (37.9)", "χ2 = 34.592; P < 0.001"], ["GBM (%)", "23 (21.9)", "GBM (%)", "38 (42.2)", "GBM (%)", "64 (62.1)"]], "row_count": 13, "column_count": 9, "numeric_cells": 43, "header_rows": 1, "locator": "section[20]/table-wrap[1]#T2"}}, {"id": "asset:table:pmid:34220791:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": 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T-cell function in the context of chronic antigen", "Inhibition of proximal TCR signaling, attenuate CD28 signaling"], ["CTLA-4", "CD152, ALPS5, CELIAC3, GRD4", "B7-1 (CD80), B7-2 (CD86)", "Activated T cells, Tregs", "Negative T-cell costimulation (primarily at priming); prevent tonic signaling, attenuate high-affinity clones", "Competitive inhibition of CD28 costimulation (binding to B7-1 and B7-2)"], ["PD-L1", "CD274, PDCD1L1, B7-H, B7H1", "PD-1, B7-1 (CD80)", "Monocytes, macrophages, mast cells, inducible in DCs, T cells, B cells, NK cells", "Attenuate T cells activity in inflamed peripheral tissues", "PD-1 ligation; cell-intrinsic mechanism unclear"], ["LAG-3", "CD223, Ly66", "MHC-II, LSECtin", "Activated CD4+ and CD8+ T cells, NK cells, Tregs", "Negative regulator of T cells expansion; control T cells homeostasis; DCs activation", "Competitive binding to MHC-II; proximal LSECtin mechanism unclear"], ["TIM-3", "HAVCR2, CD366, KIM-3, SPTCL, TIMD-3", "Galectin-9, PtdSer, HMGB1, CEACAM-1", "Th1 CD4+ and Tc1 CD8+, Tregs, DCs, NK cells, monocytes", "Negative regulation of Type immunity; preserve peripheral tolerance", "Negative regulation ofproximal TCR components; differences between ligands unknown"], ["TIGIT", "VSIG9, VSTM3, WUCAM", "PVR (CD155), PVRL2 (CD112)", "CD4+ and CD8+ T cells, Tregs, TFH, NK cells", "Inhibition of T cells activity; DC tolerization", "Competitive inhibition of DNAM1 (CD226) costimulation (binding of PVR), binding of DNAM1 in cis; cell-intrinsic ITIM-negative signaling"], ["VISTA", "VSIR, B7-H5, B7H5, C10orf54, PD-1H", "Counterreceptor unknown", "T cells and activated Tregs, myeloid cells, mature APCs", "Negative regulation of T cells activity; suppression of CD4+ T cells, shaping naive CD4+ T cells compartment", "Increase threshold for TCR signaling, induce FOXP3 synthesis; proximal signaling unknown"], ["Costimulatory", "", "", "", "", ""], ["ICOS", "AILIM, CCLP, CRP-1", "ICOSL", "Activated T cells, B cells, ILC2", "Positive costimulation; Type I and II immunity; Tregs maintenance; TFH differentiation", "p50 PI3K recruitment (AKT signaling); enhance calcium signaling (PLCγ)"], ["OX40", "TNFRSF4, ACT35, CD134, TXGP1L", "OX40L", "Activated T cells, Tregs, NK cells, NKT cells, neutrophils", "Sustain and enhance CD4+ T cell immunity; role in CD8+ T cells and Tregs", "Regulation of BCL2/XL (survival); enhance PI3K/AKT signaling"], ["GITR", "TNFRSF18, AITR, CD357, ENERGEN, GITR", "GITRL", "Activated T cells, Tregs, B cells, NK cells, macrophages", "Attenuate Tregs; costimulation of activated T cells, NK cell activation", "Signal through TRAF5"], ["CD137", "TNFRSF9, 4-1BB, CDw137, ILA", "4-1BBL (CD137L)", "Activated T cells, Tregs, NK cells, monocytes, DCs, B cells", "Positive T cells costimulation; DC activation", "Signal through TRAF1, TRAF2"], ["CD40", "TNFRSF5, Bp50, CDW40, p50", "CD40L", "APCs, B cells, monocytes, non hematopoietic cells (e.g., fibroblasts, endothelial cells)", "APC licensing", "Signal 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