Gemistocytic tumor cells programmed for glial scarring characterize T cell confinement in IDH-mutant astrocytoma

Levi Hijfte (), Marjolein Geurts, Iris Heer, Santoesha A. Ghisai, Hayri E. Balcioglu, Youri Hoogstrate, Wies R. Vallentgoed, Rania Head, Rosa Luning, Thierry Bosch, Bart Westerman, Pieter Wesseling, Johanna A. Joyce, Pim French () and Reno Debets ()
Additional contact information
Levi Hijfte: Erasmus MC Cancer Institute
Marjolein Geurts: Erasmus MC Cancer Institute
Iris Heer: Erasmus MC Cancer Institute
Santoesha A. Ghisai: Erasmus MC Cancer Institute
Hayri E. Balcioglu: Erasmus MC Cancer Institute
Youri Hoogstrate: Erasmus MC Cancer Institute
Wies R. Vallentgoed: Erasmus MC Cancer Institute
Rania Head: Erasmus MC Cancer Institute
Rosa Luning: Erasmus MC Cancer Institute
Thierry Bosch: Erasmus Medical Center
Bart Westerman: Amsterdam UMC/VUMC
Pieter Wesseling: Amsterdam UMC/VUMC and Brain Tumour Center
Johanna A. Joyce: University of Lausanne
Pim French: Erasmus MC Cancer Institute
Reno Debets: Erasmus MC Cancer Institute

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Isocitrate dehydrogenase 1/2 mutant (IDHmt) astrocytoma is considered a T cell-deprived tumor, yet little is known regarding the phenotypes underlying T cell exclusion. Using bulk, single nucleus and spatial RNA and protein profiling, we demonstrate that a distinct spatial organization underlies T cell confinement to the perivascular space (T cell cuff) in IDHmt astrocytoma. T cell cuffs are uniquely characterized by a high abundance of gemistocytic tumor cells (GTC) in the surrounding stroma. Integrative analysis shows that GTC-high tumors are enriched for lymphocytes and tumor associated macrophages (TAM) and express immune cell migration and activation programs. Specifically, GTCs constitute a distinct sub-cluster of the astrocyte-like tumor cell state that co-localizes with immune reactive TAMs. Neighboring GTCs and TAMs express receptor-ligand pairs characteristic of reactive astrogliosis and glial scarring, such as SPP1/CD44 and IL-1β/IL1R1. Collectively, we reveal that T cell confinement in IDHmt astrocytomas associates with GTC-TAM networks that mimic glial scarring mechanisms.

Date: 2025
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DOI: 10.1038/s41467-025-56441-5

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