Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF fusion pilocytic astrocytoma

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.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2024-08-13
DOI
https://doi.org/10.1172/jci177413
Citations
14
Primary Topic
Signaling Pathways in Disease
Type
article
Field-Weighted Citation Impact
3.27

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article

Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF fusion pilocytic astrocytoma

C. David James, Shashwat Tripathi, Hinda Najem, Craig Horbinski et al.
14 citations
Journal of Clinical Investigation
Signaling Pathways in Disease
3.27
article

Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF fusion pilocytic astrocytoma

C. David James, Shashwat Tripathi, Hinda Najem, Craig Horbinski, Nitin R. Wadhwani, Moloud Sooreshjani, Sebastián Pacheco, Giselle Y. López, Ganesh Rao, Sandi Lam, Roger Stupp, Michael DeCuypere, Amy B. Heimberger, Joanne Xiu, María G. Castro, Valerie I. Brown, Lisa Hurley, Ruochen Du, Theodore Nicolaides, Corey Dussold, Rimas V. Lukas, James P. Chandler, Adam M. Sonabend
article en
14 citations

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.

Journal of Clinical InvestigationVol. 134(19)
Northwestern University (US), Lurie Children's Hospital (US), Baylor College of Medicine (US), University of Michigan (US), Phoenix (United States) (US), Caris Life Sciences (United States) (US), Neurological Surgery (US), Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Penn State Milton S. Hershey Medical Center (US)
Northwestern University, Charlie Teo Foundation, National Institutes of Health, Robert H. Lurie Comprehensive Cancer Center, National Cancer Institute
Zero hunger
Openalex Percentile: Top 7%
Signaling Pathways in Disease
3.27
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