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Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF fusion pilocytic astrocytoma.
- Source :
-
Journal of Clinical Investigation . Oct2024, Vol. 134 Issue 19, p1-14. 14p. - Publication Year :
- 2024
-
Abstract
- Despite being the leading cause of cancer-related childhood mortality, pediatric gliomas have been relatively understudied, and the repurposing of immunotherapies has not been successful. Whole-transcriptome sequencing, single-cell sequencing, and sequential multiplex immunofluorescence were used to identify an immunotherapeutic strategy that could be applied to multiple preclinical glioma models. MAPK-driven pediatric gliomas have a higher IFN signature relative to other molecular subgroups. Single-cell sequencing identified an activated and cytotoxic microglia (MG) population designated MG-Act in BRAF-fused, MAPK-activated pilocytic astrocytoma (PA), but not in high-grade gliomas or normal brain. T cell immunoglobulin and mucin domain 3 (TIM3) was expressed on MG-Act and on the myeloid cells lining the tumor vasculature but not normal brain vasculature. TIM3 expression became upregulated on immune cells in the PA microenvironment, and anti-TIM3 reprogrammed ex vivo immune cells from human PAs to a proinflammatory cytotoxic phenotype. In a genetically engineered murine model of MAPK-driven, low-grade gliomas, anti-TIM3 treatment increased median survival over IgG- and anti–PD-1–treated mice. Single-cell RNA-Seq data during the therapeutic window of anti-TIM3 revealed enrichment of the MG- Act population. The therapeutic activity of anti-TIM3 was abrogated in mice on the CX3CR1 MG–KO background. These data support the use of anti-TIM3 in clinical trials of pediatric low-grade, MAPK-driven gliomas. [ABSTRACT FROM AUTHOR]
- Subjects :
- *MYELOID cells
*ASTROCYTOMAS
*CANCER-related mortality
*GLIOMAS
*SURVIVAL rate
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 134
- Issue :
- 19
- Database :
- Academic Search Index
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- 180050919
- Full Text :
- https://doi.org/10.1172/JCI177413