Gamma-aminobutyric acid-mediated neuro-immune interactions in glioblastoma: Implications for prognosis and immunotherapy response

Abstract

Aims

This study aimed to investigate the role of gamma-aminobutyric acid (GABA) in the glioblastoma (GBM) tumor immune microenvironment (TIME) and its impact on prognosis and response to immunotherapy.

Main methods

This study employed single-cell RNA sequencing (scRNA-seq) to delineate the TIME of GBM, utilized non-negative matrix factorization (NMF) for GABA-associated cell clustering, and performed pseudotime analysis for cellular trajectories. Additionally, we integrated immunohistochemistry (IHC), immunofluorescence (IF), and protein-protein interaction (PPI) analysis to explore the regulatory mechanisms within the tumor microenvironment.

Key findings

The study identified distinct GABA-associated immune cell subtypes, particularly macrophages and T-cells, with unique gene expression and developmental trajectories. The development of the GABA-associated scoring model (GABAAS), introduced novel prognostic indicators, enhancing our ability to predict patient outcomes. This study also suggests that GABA-related genes, including NDRG2 and TIMP1, play a crucial role in immune modulation, with potential implications for immunotherapy responsiveness.

Significance

The findings underscore the potential of targeting GABA-related genes (NDRG2 and TIMP1) and M2 macrophage to reshape the glioblastoma immune landscape, offering a new frontier in personalized neuro-immunotherapy. This approach holds promise to counter individual tumor immunosuppressive mechanisms, enhancing patient outcomes.