P12.37.B PROGNOSTIC MODEL STUDY BASED ON EVOLUTIONARY TRAJECTORY ANALYSIS OF GLIOMA-ASSOCIATED MACROPHAGES REVEALS THE IMMUNOTHERAPEUTIC MECHANISMS OF HISTONE DEACETYLASE INHIBITORS IN GLIOMA

Abstract BACKGROUND Glioma-associated macrophages (GAMs), originating from intracranial-resident microglia and bone marrow-derived monocytes, often exhibit pro-tumorigenic polarization within the glioma microenvironment, promoting tumor progression. This study aims to reveal the evolutionary trajectory features of GAMs from these two origins through single-cell transcriptomic analysis, construct a prognosis model based on differentiation-related genes (DRGs), screen potential targeted drugs, and investigate their therapeutic mechanisms. MATERIAL AND METHODS Single-cell transcriptome sequencing data from primary and recurrent gliomas were analyzed. Pseudotime analysis was employed to construct evolutionary trajectories of GAMs derived from microglia and monocyte lineages, identifying shared DRGs. Prognostic value of DRGs was assessed using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression in the training cohort (The Cancer Genome Atlas, TCGA). The prognostic model was validated in the test cohort (Chinese Glioma Genome Atlas, CGGA) via survival analysis and receiver operating characteristic (ROC) curves. Drug screening was performed using the Cancer Therapeutics Response Portal (CTRP). Direct/indirect co-culture models of THP1 (human monocyte-macrophage cell line) and glioblastoma cell lines were established. Phenotypic effects on GAMs and glioma cells were studied in direct co-culture, while drug mechanisms on GAM polarization were evaluated in indirect co-culture at mRNA and protein levels. RESULTS Fifteen DRGs (RPL3, TIMP1, SPP1, FABP5, EMP3, MTRNR2L8, KIF20A, CENPA, PLAUR, SMC4, HSPB1, TMSB10, GGH, CTSL, MND1) were identified to construct the prognostic model, which demonstrated robust performance in both TCGA and CGGA cohorts. Screening via CTRP prioritized a histone deacetylase (HDAC) inhibitor, Panobinostat. Three HDAC inhibitors (Panobinostat, Vorinostat, and Sodium Valproate) were tested. HDAC inhibitors suppressed glioma cell proliferation in direct co-culture and inhibited pro-tumorigenic polarization markers of GAMs at mRNA and protein levels in indirect co-culture. CONCLUSION This study highlights the prognostic value of DRGs in GAMs and identifies HDAC inhibitors as potential therapeutic agents. Mechanistically, HDAC inhibitors may impede glioma progression by suppressing pro-tumorigenic polarization of GAMs, suggesting an immunotherapeutic strategy targeting glioma-microenvironment interactions.