{"doi":"10.1172/jci177413","title":"Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF fusion pilocytic astrocytoma","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":"Journal of Clinical Investigation","year":2024,"id":431732,"datarank":0.56142919778376,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.12787343409933524,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.12787343409933524,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":15,"citers_with_citation_signal":7,"citers_with_endowment":7,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9526,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":660545,"name":"Hinda Najem","orcid":"0000-0003-4432-9708","position":1,"is_corresponding":false},{"id":1067310,"name":"Corey Dussold","orcid":null,"position":2,"is_corresponding":false},{"id":1235984,"name":"Sebastián Pacheco","orcid":"0000-0002-3235-6226","position":3,"is_corresponding":false},{"id":1049691,"name":"Ruochen Du","orcid":"0000-0002-0580-5196","position":4,"is_corresponding":false},{"id":1067309,"name":"Moloud Sooreshjani","orcid":null,"position":5,"is_corresponding":false},{"id":449298,"name":"Lisa Hurley","orcid":"0000-0001-7889-4954","position":6,"is_corresponding":false},{"id":624472,"name":"James P. 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