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

Author

Listed:
  • Adrian B. Levine

    (The Hospital for Sick Children
    University of Toronto
    The Hospital for Sick Children
    University of British Columbia)

  • Liana Nobre

    (University of Toronto
    University of Alberta)

  • Anirban Das

    (The Hospital for Sick Children
    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
    University of Toronto)

  • 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
    University of Toronto)

  • Ivana Fedoráková

    (University Children’s Hospital)

  • Vijay Ramaswamy

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Julie Bennett

    (The Hospital for Sick Children
    The Hospital for Sick Children
    Princess Margaret Cancer Centre)

  • Robert Siddaway

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Uri Tabori

    (The Hospital for Sick Children
    University of Toronto
    The Hospital for Sick Children)

  • Cynthia Hawkins

    (The Hospital for Sick Children
    University of Toronto
    The Hospital for Sick Children)

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.

Suggested Citation

  • 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 & Java, 2024. "Immuno-oncologic profiling of pediatric brain tumors reveals major clinical significance of the tumor immune microenvironment," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49595-1
    DOI: 10.1038/s41467-024-49595-1
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    References listed on IDEAS

    as
    1. Michael Schubert & Bertram Klinger & Martina Klünemann & Anja Sieber & Florian Uhlitz & Sascha Sauer & Mathew J. Garnett & Nils Blüthgen & Julio Saez-Rodriguez, 2018. "Perturbation-response genes reveal signaling footprints in cancer gene expression," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    2. Francisco Avila Cobos & José Alquicira-Hernandez & Joseph E. Powell & Pieter Mestdagh & Katleen Preter, 2020. "Author Correction: Benchmarking of cell type deconvolution pipelines for transcriptomics data," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
    3. Francisco Avila Cobos & José Alquicira-Hernandez & Joseph E. Powell & Pieter Mestdagh & Katleen De Preter, 2020. "Benchmarking of cell type deconvolution pipelines for transcriptomics data," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    4. Robert Siddaway & Scott Milos & Arun Kumaran Anguraj Vadivel & Tara H. W. Dobson & Jyothishmathi Swaminathan & Scott Ryall & Sanja Pajovic & Palak G. Patel & Javad Nazarian & Oren Becher & Michael Bru, 2022. "Splicing is an alternate oncogenic pathway activation mechanism in glioma," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    5. Sanja Pajovic & Robert Siddaway & Taylor Bridge & Javal Sheth & Patricia Rakopoulos & Byungjin Kim & Scott Ryall & Sameer Agnihotri & Lauren Phillips & Man Yu & Christopher Li & Scott Milos & Palak Pa, 2020. "Epigenetic activation of a RAS/MYC axis in H3.3K27M-driven cancer," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
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