CD93 is Associated with Glioma-related Malignant Processes and Immunosuppressive Cell Infiltration as an Inspiring Biomarker of Survivance

Abstract

Previous reports have confirmed the significance of CD93 in the progression of multiple tumors; however, there are few studies examining its immune properties for gliomas. Here, we methodically investigated the pathophysiological characteristics and clinical manifestations of gliomas. Six hundred ninety-nine glioma patients in TCGA along with 325 glioma patients in CGGA were correspondingly collected for training and validating. We analyzed and visualized total statistics using RStudio. One-way ANOVA and Student's t-test were used to assess groups' differences. All differences were considered statistically significant at the level of P < 0.05. CD93 markedly upregulated among HGG, MGMT promoter unmethylated subforms, IDH wild forms, 1p19q non-codeletion subforms, and mesenchyme type gliomas. ROC analysis illustrated the favorable applicability of CD93 in estimating mesenchyme subform. Kaplan-Meier curves together with multivariable Cox analyses upon survivance identified high-expression CD93 as a distinct prognostic variable for glioma patients. GO analysis of CD93 documented its predominant part in glioma-related immunobiological processes and inflammation responses. We examined the associations of CD93 with immune-related meta-genes, and CD93 positively correlated with HCK, LCK, MHC I, MHC II, STAT1 and IFN, while adverse with IgG. Association analyses between CD93 and gliomas-infiltrating immunocytes indicated that the infiltrating degrees of most immunocytes exhibited positive correlations with CD93, particularly these immunosuppressive subsets such as TAM, Treg, and MDSCs. CD93 is markedly associated with adverse pathology types, unfavorable survival, and immunosuppressive immunocytes infiltration among gliomas, thus identifying CD93 as a practicable marker and a promising target for glioma-based precise diagnosis and therapeutic strategies.

Keywords: Biomarker; CD93; Glioma; Immunosuppression; Prognosis; Target.

Fig. 1

CD93 expression patterns for gliomas among various WHO grades (a, b), isocitrate dehydrogenase forms (all grades (c, d), low grades (e, f), high grades (g, h)), and 1p/19q-codeletion statuses (i, j) and O⁶-methylguanine-methylguanine-deoxyribonucleic acid methyltransferases promoter statuses (k, l). CD93 is markedly upregulated among high grades, isocitrate dehydrogenase wild form, and non-codeleted 1p19q subform along with unmethylated O.⁶-methylguanine-deoxyribonucleic acid methyltransferase promoters subform gliomas. * P value below 0.05, ** P value below 0.01, *** P value below 0.001, **** P value below 0.0001

Fig. 2

Kaplan–Meier survival curvilinear analysis for CD93 among patients with overall grades (a, b), low grade (c, d), and high grade (e, f) gliomas. Highly-expressed CD93 is related to worse prognosis for patients with glioma, particularly for patients with high grades gliomas

Fig. 3

Multivariable Cox analyses of CD93 among glioma patients (a, b). High expression of CD93 is a distinct prognostic variable for patients with gliomas compared to gender, age, WHO grades and O⁶-methylguanine-deoxyribonucleic acid methyltransferases promoter statuses

Fig. 4

Relation between CD93 expression and TCGA subtypes of glioma. CD93 is indicated to be markedly upregulated in the mesenchyme subtype of both sets (a, c). Receiver operation characteristics analysis revealed the favorable applicability and accuracy of CD93 in estimating mesenchyme subform gliomas (b, d). * P value below 0.05, ** P value below 0.01, *** P value below 0.001, **** P value below 0.0001

Fig. 5

Gene ontology analysis of CD93 in gliomas among the TCGA set (a), the CGGA set (b), and the 106 overlapped genes of both sets (c, d). CD93 is closely involved in glioma-associated immune responses such as leukocyte migration, predominantly in extracellular space or on cell membranes as extracellular exosomes and membrane components

Fig. 6

Heatmap analysis of correlations among immunogene subsets and CD93 for glioma (a, b). Immunizing genes predominantly exhibit a positive correlation with CD93 for both datasets, thus revealing the role of CD93 in the context of glioma-associated immune response

Fig. 7

Inflammation-related functions of CD93 among gliomas. Heatmap analysis of correlations of inflammatory genes with CD93 expression (a, b). Genes set variant analysis of CD93 and inflammatory metagenes (c, d). Blue indicates positive correlation, while red indicates negative correlation. Bicolor gradation together with the circle dimension are in proportion to correlational degree. CD93 expression is significantly positively correlated with hematopoietic cell kinase (HCK), lymphocyte-specific protein tyrosine kinase (LCK), major histocompatibility complex (MHC) I, MHC II, signal transducer and activator of transcription 1 (STAT1), and interferon (IFN), while immunoglobulin G (IgG) is negatively correlated

Fig. 8

Associations analyses of CD93 and gliomas-infiltrating immunocytes. Corrgram analyses visualizing associations of CD93 with six major tumor-infiltrating immunocyte subpopulations (a, b). Blue indicates positive correlation, while red indicates negative correlation. Bicolor gradation together with the circle dimension are in proportion to correlation degree. The leading diagonal contains the minimum and maximum values of the variables. Pearson associations analyses of CD93 and tumor-associated macrophages (TAMs) (c, f), regulatory T lymphocytes (Tregs) (d, g) and myeloid-derived suppressor cells (MDSCs) (e, h) among the two datasets. Cases of glioma are displayed as dots, and regression analyzing lines are added into corresponding points in the diagram