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

Nat Commun. 2025 Jan 29;16(1):1156. doi: 10.1038/s41467-025-56441-5.

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.

MeSH terms

  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Astrocytoma* / genetics
  • Astrocytoma* / immunology
  • Astrocytoma* / pathology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / immunology
  • Brain Neoplasms / pathology
  • Cell Movement
  • Gliosis / genetics
  • Gliosis / pathology
  • Humans
  • Isocitrate Dehydrogenase* / genetics
  • Isocitrate Dehydrogenase* / metabolism
  • Mutation*
  • T-Lymphocytes* / immunology
  • T-Lymphocytes* / metabolism
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology
  • Tumor-Associated Macrophages / immunology
  • Tumor-Associated Macrophages / metabolism

Substances

  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • IDH2 protein, human