TMIC-98. Single-cell profiling of peripheral and local immune compartments reveal unique genotype- independent prognostic immune signatures across IDH-stratified glioma

Abstract BACKGROUND Glioma immune suppression involves both local and systemic mechanisms that vary by tumor genotype. While prior studies have characterized the tumor immune microenvironment (TIME), the interplay between peripheral and intratumoral immune responses across glioma genotypes remains poorly defined. We aimed to characterize local and circulating immune ontogenies across isocitrate dehydrogenase-mutant (IDH-Mut) and IDH-wildtype (IDH-WT) gliomas and evaluate their prognostic relevance. METHODS We performed paired single-cell RNA sequencing (scRNA-seq) of tumor-infiltrating leukocytes and peripheral blood mononuclear cells (PBMCs) from 18 adult glioma patients (6 IDH-Mut, 12 IDH-WT). Immune cell subsets were validated using spectral flow cytometry. We applied transcriptomic deconvolution to The Cancer Genome Atlas (TCGA) datasets to evaluate survival associations. RESULTS IDH-stratified gliomas exhibited distinct immune compositions in both the TIME and PBMCs. IDH-Mut patients showed enrichment of naïve CD4+ T cells and a unique population of GZMH+ CD8+ T cells in both compartments, whereas IDH-WT patients displayed elevated monocytes and Tregs. Notably, we identified microglia-like cells in peripheral blood expressing P2RY12 and CD83, absent in healthy controls and inducible by glioma-conditioned media. Transcriptomic deconvolution of TCGA data using single-cell references revealed five immune clusters with distinct cellular compositions. These immune clusters were predictive of overall survival independently of IDH status and common glioma mutations. CD83+C1Qhi microglia emerged as key mediators of immune communication, interacting broadly with T and myeloid cells and serving as dominant TNF signalers in IDH-Mut tumors. CONCLUSIONS This study uncovers shared and genotype-specific immune programs across the tumor and blood compartments of glioma patients. Immune-based transcriptional signatures, including those derived from peripheral blood, serve as independent predictors of survival. These findings establish a foundation for developing immune-based diagnostics and immunotherapies tailored to glioma genotype and immune contexture.