Gemistocytic tumor cells programmed for glial scarring characterize T cell confinement in IDH-mutant astrocytoma
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 unde...
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| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56441-5 |
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| Summary: | 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. |
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| ISSN: | 2041-1723 |