%0 Journal Article
%T Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF-Fusion pilocytic astrocytoma.
%A Tripathi S
%A Najem H
%A Dussold C
%A Pacheco S
%A Du R
%A Sooreshjani M
%A Hurley LA
%A Chandler JP
%A Stupp R
%A Sonabend AM
%A Horbinski CM
%A Lukas RV
%A Xiu J
%A López GY
%A Nicolaides TP
%A Brown V
%A Wadhwani NR
%A Lam SK
%A James CD
%A Rao G
%A Castro MG
%A Heimberger AB
%A DeCuypere M
%J J Clin Invest
%V 0
%N 0
%D 2024 Aug 13
%M 39137048
%F 19.456
%R 10.1172/JCI177413
%X Despite being the leading cause of 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 immunotherapy strategy evaluated in multiple preclinical glioma models. MAPK-driven pediatric gliomas have a higher interferon signature relative to other molecular subgroups. Single-cell sequencing identified an activated and cytotoxic microglia population designated MG-Act in BRAF-fused MAPK-activated pilocytic astrocytoma (PA), but not in high-grade gliomas or normal brain. TIM3 is expressed on MG-Act and on the myeloid cells lining the tumor vasculature but not normal brain. TIM3 expression becomes upregulated on immune cells in the PA microenvironment and anti-TIM3 reprograms ex vivo immune cells from human PAs to a pro-inflammatory cytotoxic phenotype. In a genetically engineered murine model of MAPK-driven low-grade gliomas, anti-TIM3 treatment increased median survival over IgG and anti-PD1 treated mice. ScRNA sequencing data during the therapeutic window of anti-TIM3 demonstrates enrichment of the MG-Act population. The therapeutic activity of anti-TIM3 is abrogated in the CX3CR1 microglia knockout background. These data support the use of anti-TIM3 in clinical trials of pediatric low-grade MAPK-driven gliomas.