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MAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas

Author

Listed:
  • Romain Sigaud

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT))

  • Thomas K. Albert

    (University Children’s Hospital Münster)

  • Caroline Hess

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University)

  • Thomas Hielscher

    (Division of Biostatistics, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK))

  • Nadine Winkler

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University)

  • Daniela Kocher

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University)

  • Carolin Walter

    (University of Münster)

  • Daniel Münter

    (University Children’s Hospital Münster)

  • Florian Selt

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University Hospital)

  • Diren Usta

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University Hospital)

  • Jonas Ecker

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University Hospital)

  • Angela Brentrup

    (University Hospital Münster)

  • Martin Hasselblatt

    (University Hospital Münster)

  • Christian Thomas

    (University Hospital Münster)

  • Julian Varghese

    (University of Münster)

  • David Capper

    (Berlin Institute of Health
    Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology)

  • Ulrich W. Thomale

    (Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Neurosurgery)

  • Pablo Hernáiz Driever

    (Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, German HIT-LOGGIC-Registry for pLGG in children and adolescents, Department of Pediatric Oncology and Hematology)

  • Michèle Simon

    (Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, German HIT-LOGGIC-Registry for pLGG in children and adolescents, Department of Pediatric Oncology and Hematology)

  • Svea Horn

    (Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, German HIT-LOGGIC-Registry for pLGG in children and adolescents, Department of Pediatric Oncology and Hematology)

  • Nina Annika Herz

    (Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, German HIT-LOGGIC-Registry for pLGG in children and adolescents, Department of Pediatric Oncology and Hematology)

  • Arend Koch

    (Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology)

  • Felix Sahm

    (Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Stefan Hamelmann

    (Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Augusto Faria-Andrade

    (McGill University)

  • Nada Jabado

    (McGill University
    McGill University
    McGill University, and The Research Institute of the McGill University Health Centre)

  • Martin U. Schuhmann

    (University Hospital Tübingen)

  • Antoinette Y. N. Schouten-van Meeteren

    (Princess Màxima Center for Pediatric Oncology)

  • Eelco Hoving

    (Princess Màxima Center for Pediatric Oncology)

  • Tilman Brummer

    (University of Freiburg and German Consortium for Translational Cancer Research (DKTK), Freiburg, Germany, German Cancer Research Center (DKFZ))

  • Cornelis M. Tilburg

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University Hospital)

  • Stefan M. Pfister

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    National Center for Tumor Diseases (NCT)
    Heidelberg University Hospital
    Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Olaf Witt

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University Hospital)

  • David T. W. Jones

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Research Center (DKFZ))

  • Kornelius Kerl

    (University Children’s Hospital Münster)

  • Till Milde

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University Hospital)

Abstract

Pediatric low-grade gliomas (pLGG) show heterogeneous responses to MAPK inhibitors (MAPKi) in clinical trials. Thus, more complex stratification biomarkers are needed to identify patients likely to benefit from MAPKi therapy. Here, we identify MAPK-related genes enriched in MAPKi-sensitive cell lines using the GDSC dataset and apply them to calculate class-specific MAPKi sensitivity scores (MSSs) via single-sample gene set enrichment analysis. The MSSs discriminate MAPKi-sensitive and non-sensitive cells in the GDSC dataset and significantly correlate with response to MAPKi in an independent PDX dataset. The MSSs discern gliomas with varying MAPK alterations and are higher in pLGG compared to other pediatric CNS tumors. Heterogenous MSSs within pLGGs with the same MAPK alteration identify proportions of potentially sensitive patients. The MEKi MSS predicts treatment response in a small set of pLGG patients treated with trametinib. High MSSs correlate with a higher immune cell infiltration, with high expression in the microglia compartment in single-cell RNA sequencing data, while low MSSs correlate with low immune infiltration and increased neuronal score. The MSSs represent predictive tools for the stratification of pLGG patients and should be prospectively validated in clinical trials. Our data supports a role for microglia in the response to MAPKi.

Suggested Citation

  • Romain Sigaud & Thomas K. Albert & Caroline Hess & Thomas Hielscher & Nadine Winkler & Daniela Kocher & Carolin Walter & Daniel Münter & Florian Selt & Diren Usta & Jonas Ecker & Angela Brentrup & Mar, 2023. "MAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40235-8
    DOI: 10.1038/s41467-023-40235-8
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