TMIC-69. Macrophage-associated genes as prognostic biomarkers in mesenchymal glioblastoma

Abstract BACKGROUND: Glioblastoma (GBM) is a highly heterogeneous and aggressive brain cancer, classified into classical (CL), proneural (PN) and mesenchymal (ME). ME GBMs are characterized by higher levels of tumor-associated macrophage (TAM) infiltration, which drives immunosuppression and tumor progression. This study investigates whether macrophage gene signatures can serve as prognostic biomarkers across GBM subtypes. METHODS: RNA-seq data from 288 GBM patients in The Cancer Genome Atlas (TCGA) were analysed. Macrophage-related gene sets were curated from MSigDB and evaluated using pairwise Gene Set Enrichment Analysis (GSEA). The gene set CUI_DEVELOPING_HEART_C8_MACROPHAGE (275 genes), derived from single-cell RNA-seq of fetal macrophages, was most enriched in ME GBMs and selected for survival analysis. Kaplan-Meier analysis using median stratification identified the five most prognostic genes, which were then evaluated using Cox regression. RESULTS: Distinct macrophage profiles were observed: ME GBMs were TAM-rich, with mixed M1/M2 characteristics; CL GBMs displayed enrichment in tissue-resident macrophage subsets (e.g. APOE+); while PN GBMs were not enriched. High expression of RETN (Resistin), LSP1 (Lymphocyte-specific protein 1) and CTSB (Cathepsin B) was significantly associated with poor survival in both univariate and multivariate Cox models across all subtypes (RETN: HR = 1.036, p = 0.0088; LSP1: HR = 1.017, p = 0.0104; CTSB: HR = 1.001, p = 0.0094). High-expression groups had shorter median survival (357-375 days vs 448-466 days) and lower 2-year overall survival (16.2-17.9% vs 30.1-32.5%). These genes contribute to TAM-driven immunosuppression: RETN dampens anti-tumor immunity, LSP1 promotes macrophage chemotaxis and CTSB facilitates invasion and immune evasion. CONCLUSION: RETN, LSP1 and CTSB are robust prognostic biomarkers in GBM. While CTSB has been linked to invasion and mesenchymal transition in gliomas, RETN and LSP1 have emerged as modulators of immunosuppression. These genes are promising candidates for TAM-targeted therapies against glioblastoma and patient prognostication across subtypes.