Distinct tumor-TAM interactions in IDH-stratified glioma microenvironments unveiled by single-cell and spatial...

Area of Science:

• Neuro-oncology
• Immunology
• Cancer Biology

Background:

• Tumor-associated macrophages (TAMs) critically influence the tumor microenvironment (TME), impacting tumor progression, immunity, and remodeling.
• Comparative analysis of tumor-TAM crosstalk across IDH-defined glioma subtypes is lacking, potentially explaining varied clinical trial outcomes.

Purpose of the Study:

• To delineate TAM phenotypic heterogeneity in IDH-stratified gliomas.
• To identify distinct tumor-TAM crosstalk mechanisms in IDH-wildtype (IDH-WT) glioblastoma (GBM).
• To uncover potential therapeutic targets and understand recurrence patterns in glioma-associated TAMs.

Main Methods:

• Phenotypic characterization of TAMs across IDH-stratified gliomas.
• Inference of gene regulatory networks and analysis of reciprocal tumor-TAM interactions.
• Spatially resolved transcriptomics, bulk RNA-seq, and RT-qPCR for gene expression analysis.

Main Results:

• Two mesenchymal TAM subsets enriched in IDH-WT GBM correlated with poorer survival and reduced anti-PD-1 response.
• SLAMF9 receptor identified as a potential therapeutic target.
• Key crosstalk pathways (e.g., ANXA1-FPR1/3, FN1-ITGAVB1) identified in IDH-WT tumors contribute to immunosuppression and invasion.
• Upregulation of ANXA1, FN1, NRP1, and TNFRSF12A confirmed in IDH-WT tumors; expression remained stable between primary and recurrent tumors.

Conclusions:

• Distinct TAM phenotypes and crosstalk mechanisms exist in IDH-WT GBM, presenting therapeutic vulnerabilities.
• SLAMF9, ANXA1, FN1, NRP1, and TNFRSF12A represent potential targets for IDH-WT GBM treatment.
• The tumor-TAM interactive network is largely conserved from primary to recurrent IDH-WT glioma.