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. 2025 Sep 20:noaf206.
doi: 10.1093/neuonc/noaf206. Online ahead of print.

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

Jonathan H Sussman  1   2 , Anthony R Cillo  3   4   5   6 , Sajeev Kohli  1   7 , Carly Cardello  3   4 , Jonathan Patterson  1 , Ebrar Akca  1 , Angelo Angione  1 , David Moon  1   7 , Katharine Krueger  1 , Ali Ghamari  1 , Emily Xu  1 , Jessica Xu  2   6 , Antonio C Tarbay  1 , Alex Li  2   6 , Bhargavi R Budihal  1   8 , Xiaoran Zhang  3   4 , Omar Elghawy  9 , Wojciech K Panek  10 , Prajwal Rajappa  11   12   13 , Kai Tan  14   15 , Dario A A Vignali  3   4   5 , Tullia C Bruno  3   4   5 , Nduka M Amankulor  1   16
Affiliations

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

Jonathan H Sussman et al. Neuro Oncol. .

Abstract

Background: Solid tumor immune suppression requires cooperation of tumor cells, local immune cells, peripheral circulating immune cells, and evolution of immune cell trajectories between peripheral and local environments. This study addresses a significant knowledge gap by characterizing peripheral and local immune environments in IDH Mutant (IDH-Mut) and IDH wildtype (IDH-WT) gliomas and defines novel immunological states with prognostic relevance across the glioma landscape.

Methods: We analyzed local and peripheral immune phenotypes in a cohort of 18 (6 IDH-Mut and 12 IDH-WT) gliomas with distinct genetic characteristics using paired human tumor and peripheral blood mononuclear cells (PBMCs) with single-cell RNA-sequencing (scRNA-seq).

Results: Our analyses revealed unique intratumoral and peripheral immune cellular ontogenies, including naïve CD4+ T cell enrichment in the IDH-Mut peripheral immune compartment, monocyte enrichment in IDH-WT glioma PBMCs, and emergence of a unique population of GZMH+ CD8+ T cells preferentially in the IDH-Mut microenvironment. Additionally, we found upregulation of TNF-α signaling and inflammatory response pathways in IDH-Mut-glioma-associated peripheral lymphoid cells versus IDH-WT tumors and identified a novel population of microglia-like cells in the peripheral blood of glioma patients with complement-interfacing characteristics. Applying intratumoral transcriptomic deconvolution via The Cancer Genome Atlas revealed genotype-independent, prognostic immune signatures across the malignant glioma landscape.

Conclusions: This study reveals variable expression of immune phenotypes in adult gliomas stratified by IDH status and characterizes immune compartment and genotype-dependent differences in the immunologic glioma landscape. These genotype-dependent, tumor and circulating immune ontogenies should guide future diagnostic and immunotherapeutic considerations in malignant glioma.

Keywords: IDH Mutant glioma; circulating immune cells; immunotherapy; single-cell sequencing; tumor immune microenvironment.

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