2. Academic Validation
  3. Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF fusion pilocytic astrocytoma

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

  • J Clin Invest. 2024 Aug 13;134(19):e177413. doi: 10.1172/JCI177413.
Shashwat Tripathi 1 2,  Hinda Najem 1 2,  Corey Dussold 1 2,  Sebastian Pacheco 1 2,  Ruochen Du 1 2,  Moloud Sooreshjani 1 2,  Lisa Hurley 1 2,  James P Chandler 1 2,  Roger Stupp 1 2,  Adam M Sonabend 1 2,  Craig M Horbinski 2 3,  Rimas V Lukas 1 2,  Joanne Xiu 4,  Giselle Lopez 4,  Theodore P Nicolaides 4,  Valerie Brown 5,  Nitin R Wadhwani 6,  Sandi K Lam 1 2 7,  Charles David James 1 2,  Ganesh Rao 8,  Maria G Castro 9,  Amy B Heimberger 1 2,  Michael DeCuypere 1 2 7
Affiliations

Affiliations

  • 1 Department of Neurological Surgery.
  • 2 Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, and.
  • 3 Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
  • 4 Caris Life Sciences, Phoenix, Arizona, USA.
  • 5 Department of Pediatrics, Penn State Cancer Institute, Hershey, Pennsylvania, USA.
  • 6 Department of Pathology and Laboratory Medicine.
  • 7 Division of Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
  • 8 Department of Neurosurgery, Baylor College of Medicine, Houston Texas, USA.
  • 9 Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.
PMID: 39137048 DOI: 10.1172/JCI177413
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.

Keywords

Brain cancer; Cancer immunotherapy; Immunology; Oncology.

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