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<p>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&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月29日

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  • 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

摘要

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.