Molecular immune signature identifies microglia and NK cell infiltration as a favorable prognostic marker in adult-type high-grade glioma

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. Previous article in issue