Publication Date
8-13-2024
Journal
Journal of Clinical Investigation
DOI
10.1172/JCI177413
PMID
39137048
PMCID
PMC11444160
PubMedCentral® Posted Date
8-13-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Hepatitis A Virus Cellular Receptor 2, Humans, Animals, Mice, Proto-Oncogene Proteins B-raf, Astrocytoma, Child, Brain Neoplasms, Female, Tumor Microenvironment, Male, Neoplasm Proteins, Glioma
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.
Included in
Immunotherapy Commons, Medical Immunology Commons, Mental and Social Health Commons, Neurology Commons, Neurosciences Commons, Oncology Commons