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ResearchIn-Press PreviewImmunologyOncology Open Access | 10.1172/JCI177413

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

Shashwat Tripathi,1 Hinda Najem,1 Corey Dussold,1 Sebastian Pacheco,1 Ruochen Du,1 Moloud Sooreshjani,1 Lisa A. Hurley,1 James P. Chandler,1 Roger Stupp,1 Adam M. Sonabend,1 Craig M. Horbinski,2 Rimas V. Lukas,1 Joanne Xiu,3 Giselle Y. López,3 Theodore P. Nicolaides,3 Valerie Brown,4 Nitin R. Wadhwani,5 Sandi K. Lam,1 Charles David James,1 Ganesh Rao,6 Maria G. Castro,7 Amy B. Heimberger,1 and Michael DeCuypere1

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Tripathi, S. in: PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Du, R. in: PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Sooreshjani, M. in: PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Brown, V. in: PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Wadhwani, N. in: PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Lam, S. in: PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by James, C. in: PubMed | Google Scholar |

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Rao, G. in: PubMed | Google Scholar

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Castro, M. in: PubMed | Google Scholar |

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Heimberger, A. in: PubMed | Google Scholar |

1Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer C, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

3Caris Life Sciences, Phoenix, United States of America

4Department of Pediatrics, Penn State Cancer Institute, Hershey, United States of America

5Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States of America

6Department of Neurosurgery, Baylor College of Medicine, Houston, United States of America

7Department of Neurological Surgery, University of Michigan Medical School, Ann Arbor, United States of America

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Published August 13, 2024 - More info

J Clin Invest. https://doi.org/10.1172/JCI177413.
Copyright © 2024, Tripathi et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 13, 2024 - Version history
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Abstract

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.

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  • Version 1 (August 13, 2024): In-Press Preview
  • Version 2 (October 1, 2024): Electronic publication
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