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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56441-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832571505775476736 |
|---|---|
| author | Levi van Hijfte Marjolein Geurts Iris de Heer Santoesha A. Ghisai Hayri E. Balcioglu Youri Hoogstrate Wies R. Vallentgoed Rania Head Rosa Luning Thierry van den Bosch Bart Westerman Pieter Wesseling Johanna A. Joyce Pim French Reno Debets |
| author_facet | Levi van Hijfte Marjolein Geurts Iris de Heer Santoesha A. Ghisai Hayri E. Balcioglu Youri Hoogstrate Wies R. Vallentgoed Rania Head Rosa Luning Thierry van den Bosch Bart Westerman Pieter Wesseling Johanna A. Joyce Pim French Reno Debets |
| author_sort | Levi van Hijfte |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3bd3dbf64bec4584a78abb6773225ae7 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3bd3dbf64bec4584a78abb6773225ae72025-02-02T12:31:08ZengNature PortfolioNature Communications2041-17232025-01-0116111610.1038/s41467-025-56441-5Gemistocytic tumor cells programmed for glial scarring characterize T cell confinement in IDH-mutant astrocytomaLevi van Hijfte0Marjolein Geurts1Iris de Heer2Santoesha A. Ghisai3Hayri E. Balcioglu4Youri Hoogstrate5Wies R. Vallentgoed6Rania Head7Rosa Luning8Thierry van den Bosch9Bart Westerman10Pieter Wesseling11Johanna A. Joyce12Pim French13Reno Debets14Department of Neurology, Erasmus MC Cancer InstituteDepartment of Neurology, Erasmus MC Cancer InstituteDepartment of Neurology, Erasmus MC Cancer InstituteDepartment of Neurology, Erasmus MC Cancer InstituteDepartment of Medical Oncology, Laboratory of Tumor Immunology, Erasmus MC Cancer InstituteDepartment of Neurology, Erasmus MC Cancer InstituteDepartment of Neurology, Erasmus MC Cancer InstituteDepartment of Neurology, Erasmus MC Cancer InstituteDepartment of Neurology, Erasmus MC Cancer InstituteDepartment of Pathology, Erasmus Medical CenterDepartment of Neurosurgery, Amsterdam UMC/VUMCDepartment of Pathology, Amsterdam UMC/VUMC and Brain Tumour CenterDepartment of Oncology, University of LausanneDepartment of Neurology, Erasmus MC Cancer InstituteDepartment of Medical Oncology, Laboratory of Tumor Immunology, Erasmus MC Cancer InstituteAbstract 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.https://doi.org/10.1038/s41467-025-56441-5 |
| spellingShingle | Levi van Hijfte Marjolein Geurts Iris de Heer Santoesha A. Ghisai Hayri E. Balcioglu Youri Hoogstrate Wies R. Vallentgoed Rania Head Rosa Luning Thierry van den Bosch Bart Westerman Pieter Wesseling Johanna A. Joyce Pim French Reno Debets Gemistocytic tumor cells programmed for glial scarring characterize T cell confinement in IDH-mutant astrocytoma Nature Communications |
| title | Gemistocytic tumor cells programmed for glial scarring characterize T cell confinement in IDH-mutant astrocytoma |
| title_full | Gemistocytic tumor cells programmed for glial scarring characterize T cell confinement in IDH-mutant astrocytoma |
| title_fullStr | Gemistocytic tumor cells programmed for glial scarring characterize T cell confinement in IDH-mutant astrocytoma |
| title_full_unstemmed | Gemistocytic tumor cells programmed for glial scarring characterize T cell confinement in IDH-mutant astrocytoma |
| title_short | Gemistocytic tumor cells programmed for glial scarring characterize T cell confinement in IDH-mutant astrocytoma |
| title_sort | gemistocytic tumor cells programmed for glial scarring characterize t cell confinement in idh mutant astrocytoma |
| url | https://doi.org/10.1038/s41467-025-56441-5 |
| work_keys_str_mv | AT levivanhijfte gemistocytictumorcellsprogrammedforglialscarringcharacterizetcellconfinementinidhmutantastrocytoma AT marjoleingeurts gemistocytictumorcellsprogrammedforglialscarringcharacterizetcellconfinementinidhmutantastrocytoma AT irisdeheer gemistocytictumorcellsprogrammedforglialscarringcharacterizetcellconfinementinidhmutantastrocytoma AT santoeshaaghisai gemistocytictumorcellsprogrammedforglialscarringcharacterizetcellconfinementinidhmutantastrocytoma AT hayriebalcioglu gemistocytictumorcellsprogrammedforglialscarringcharacterizetcellconfinementinidhmutantastrocytoma AT yourihoogstrate gemistocytictumorcellsprogrammedforglialscarringcharacterizetcellconfinementinidhmutantastrocytoma AT wiesrvallentgoed gemistocytictumorcellsprogrammedforglialscarringcharacterizetcellconfinementinidhmutantastrocytoma AT raniahead gemistocytictumorcellsprogrammedforglialscarringcharacterizetcellconfinementinidhmutantastrocytoma AT rosaluning gemistocytictumorcellsprogrammedforglialscarringcharacterizetcellconfinementinidhmutantastrocytoma AT thierryvandenbosch gemistocytictumorcellsprogrammedforglialscarringcharacterizetcellconfinementinidhmutantastrocytoma AT bartwesterman gemistocytictumorcellsprogrammedforglialscarringcharacterizetcellconfinementinidhmutantastrocytoma AT pieterwesseling gemistocytictumorcellsprogrammedforglialscarringcharacterizetcellconfinementinidhmutantastrocytoma AT johannaajoyce gemistocytictumorcellsprogrammedforglialscarringcharacterizetcellconfinementinidhmutantastrocytoma AT pimfrench gemistocytictumorcellsprogrammedforglialscarringcharacterizetcellconfinementinidhmutantastrocytoma AT renodebets gemistocytictumorcellsprogrammedforglialscarringcharacterizetcellconfinementinidhmutantastrocytoma |