Immuno-oncologic profiling of pediatric brain tumors reveals major clinical significance of the tumor immune microenvironment

Adrian B. Levine, Liana Nobre, Anirban Das, Scott Milos, Vanessa Bianchi, Monique Johnson, Nicholas R. Fernandez, Lucie Stengs, Scott Ryall, Michelle Ku, Mansuba Rana, Benjamin Laxer, Javal Sheth, Stefanie-Grace Sbergio, Ivana Fedoráková, Vijay Ramaswamy, Julie Bennett, Robert Siddaway, Uri Tabori and Cynthia Hawkins ()
Additional contact information
Adrian B. Levine: The Hospital for Sick Children
Liana Nobre: University of Toronto
Anirban Das: The Hospital for Sick Children
Scott Milos: The Hospital for Sick Children
Vanessa Bianchi: The Hospital for Sick Children
Monique Johnson: The Hospital for Sick Children
Nicholas R. Fernandez: The Hospital for Sick Children
Lucie Stengs: The Hospital for Sick Children
Scott Ryall: The Hospital for Sick Children
Michelle Ku: The Hospital for Sick Children
Mansuba Rana: The Hospital for Sick Children
Benjamin Laxer: The Hospital for Sick Children
Javal Sheth: The Hospital for Sick Children
Stefanie-Grace Sbergio: The Hospital for Sick Children
Ivana Fedoráková: University Children’s Hospital
Vijay Ramaswamy: The Hospital for Sick Children
Julie Bennett: The Hospital for Sick Children
Robert Siddaway: The Hospital for Sick Children
Uri Tabori: The Hospital for Sick Children
Cynthia Hawkins: The Hospital for Sick Children

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract With the success of immunotherapy in cancer, understanding the tumor immune microenvironment (TIME) has become increasingly important; however in pediatric brain tumors this remains poorly characterized. Accordingly, we developed a clinical immune-oncology gene expression assay and used it to profile a diverse range of 1382 samples with detailed clinical and molecular annotation. In low-grade gliomas we identify distinct patterns of immune activation with prognostic significance in BRAF V600E-mutant tumors. In high-grade gliomas, we observe immune activation and T-cell infiltrates in tumors that have historically been considered immune cold, as well as genomic correlates of inflammation levels. In mismatch repair deficient high-grade gliomas, we find that high tumor inflammation signature is a significant predictor of response to immune checkpoint inhibition, and demonstrate the potential for multimodal biomarkers to improve treatment stratification. Importantly, while overall patterns of immune activation are observed for histologically and genetically defined tumor types, there is significant variability within each entity, indicating that the TIME must be evaluated as an independent feature from diagnosis. In sum, in addition to the histology and molecular profile, this work underscores the importance of reporting on the TIME as an essential axis of cancer diagnosis in the era of personalized medicine.

Date: 2024
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DOI: 10.1038/s41467-024-49595-1

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