Distinct Immune Microenvironment Associated With Long-Term Survival in High-Grade Glioma

Key Clinical Summary:

• Design/Population: This translational analysis evaluated immune gene expression, DNA methylation–based immune cell composition, and immunohistochemistry in 48 patients with high-grade glioma. Comparisons were made between long-term and short-term survivors.
• Key Outcomes: Long-term survival was associated with increased NK cell infiltration and activated microglia, along with upregulation of immune surveillance and antigen presentation pathways. In contrast, short-term survival was associated with increased M1-like macrophages and less favorable immune profiles.
• Clinical Relevance: These findings highlight the importance of the tumor immune microenvironment in glioma outcomes. Immune signatures may serve as prognostic biomarkers and guide future immunotherapy strategies.

Results from a translational analysis suggest that long-term survival in patients with high-grade glioma is associated with a distinct immune microenvironment characterized by enhanced natural killer (NK) cell activity and microglial activation. 

“High-grade gliomas represent the most common primary central nervous system malignancies, accounting for more than half of all malignant primary brain cancers,” stated Monica Patanè, PhD, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy, and coauthors. “Despite significant advances in multimodal treatment strategies… the prognosis for patients with [high-grade gliomas], particularly those with IDH-wildtype glioblastoma multiforme, remains poor.”

In this study, investigators analyzed tumor samples from 48 adult patients, including 32 long-term survivors and 16 short-term survivors. Immune-related gene expression was assessed using the NanoString platform, immune cell composition was evaluated through DNA methylation-based immune cell deconvolution, and findings were validated with immunohistochemistry. 

Gene expression profiling of 730 immune-related genes identified 102 differentially expressed genes between long-term survivors and short-term survivors (P < 0.05).  Among these, 10 genes were upregulated in long-term survivors and were associated with immune surveillance and activation, including pathways involving NK cell function, antigen presentation, and cytokine signaling. Key genes included HLA-DQA1, LAMP1/3, CD180, NOSA2A, IL12A, IL3RA, and OSM. 

Immune cell deconvolution demonstrated increased NK cell infiltration and decreased memory T-cell populations in long-term survivors. Immunohistochemistry confirmed enrichment of NK cells and activated microglia in long-term survivors, both of which were associated with improved survival. In contrast, M1-like macrophages were abundant in short-term survivors. 

Further anaylsis, revealed that higher NK cell abundance was significantly associated with improved overall survival. Activated microglia, assessed by IBA1 expression, were also associated with prolonged survival. 

“These integrated findings underscore the beneficial immune microenvironment in [long-term survivors with high-grade gliomas] driven by specific innate and adaptive immune components,” concluded Dr Pantane et al. “This immune signature may serve as a prognostic indicator and guide immunomodulatory therapeutic strategies for gliomas.” 

Source:

Patanè M, Abballe L, Patrizi S, et al. Molecular immune signature identifies microglia and NK cell infiltration as a favorable prognostic marker in adult-type high-grade glioma. ESMO Open. Published online: March 17, 2026. doi:10.1016/j.esmoop.2026.106902