Abstract
BACKGROUND: High-grade gliomas (HGG) are aggressive central nervous system tumors with poor outcomes; in fact, only a small subset of patients survive beyond 5 years. METHODS: To investigate the biological features associated with 5-year-long-term survival (LTS), we profiled immune-related gene expression using the NanoString nCounter platform, assessed immune cell composition via DNA methylation-based deconvolution, and validated the findings using immunohistochemistry. RESULTS: Gene expression profiling of 730 immune-related genes revealed 102 differentially expressed genes (q < 0.05) between LTS and short-term survivors (STS), with 10 up-regulated and 92 downregulated genes in LTS. The genes up-regulated in LTS were primarily associated with enhanced immune surveillance and regulation, including microglial and natural killer (NK) cell activity. Notably, elevated expression of HLA-DQA1 (adaptive immunity), LAMP1/3 (antigen processing), CD180 (TAM-associated TLR), and cytokine regulators such as NOS2A, IL12A, IL3RA, and OSM suggest the occurrence of a robust and coordinated immune response. Immune cell deconvolution from DNA methylation data identified increased NK cells and decreased (CD4+, CD45RA-, and CD45RO+) memory T cells in LTS, whereas immunohistochemistry confirmed the enrichment of NK cells and activated microglia, both positively associated with survival. Conversely, M1-like macrophages were more abundant in STS tumors. CONCLUSIONS: These integrated findings underscore the beneficial immune microenvironment in LTS HGG driven by specific innate and adaptive immune components. This immune signature may serve as a prognostic indicator and guide immunomodulatory therapeutic strategies for gliomas.