1. Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF fusion pilocytic astrocytoma
- Author
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Tripathi, Shashwat, Najem, Hinda, Dussold, Corey, Pacheco, Sebastian, Du, Ruochen, Sooreshjani, Moloud, Hurley, Lisa, Chandler, James P., Stupp, Roger, Sonabend, Adam M., Horbinski, Craig M., Lukas, Rimas V., Xiu, Joanne, Lopez, Giselle, Nicolaides, Theodore P., Brown, Valerie, Wadhwani, Nitin R., Lam, Sandi K., James, Charles David, Rao, Ganesh, Castro, Maria G., Heimberger, Amy B., and DeCuypere, Michael
- Subjects
RNA sequencing -- Usage ,Astrocytoma -- Diagnosis -- Genetic aspects -- Care and treatment ,Brain tumors -- Diagnosis -- Genetic aspects -- Care and treatment ,Chromosomal proteins -- Identification and classification -- Health aspects ,Tumors in children -- Diagnosis -- Genetic aspects -- Care and treatment ,Pediatric research ,Health care industry - 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 MGAct 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., Introduction Immunological studies of adult gliomas have been numerous, whereas pediatric gliomas are relatively understudied despite the fact that they are the leading cause of cancer-related childhood mortality (1). Among [...]
- Published
- 2024
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