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

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, Martin Hasselblatt, Christian Thomas, Julian Varghese, David Capper, Ulrich W. Thomale, Pablo Hernáiz Driever, Michèle Simon, Svea Horn, Nina Annika Herz, Arend Koch, Felix Sahm, Stefan Hamelmann, Augusto Faria-Andrade, Nada Jabado, Martin U. Schuhmann, Antoinette Y. N. Schouten- van Meeteren, Eelco Hoving, Tilman Brummer, Cornelis M. Tilburg, Stefan M. Pfister, Olaf Witt, David T. W. Jones, Kornelius Kerl and Till Milde ()
Additional contact information
Romain Sigaud: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Thomas K. Albert: University Children’s Hospital Münster
Caroline Hess: Hopp Children’s Cancer Center Heidelberg (KiTZ)
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)
Daniela Kocher: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Carolin Walter: University of Münster
Daniel Münter: University Children’s Hospital Münster
Florian Selt: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Diren Usta: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Jonas Ecker: Hopp Children’s Cancer Center Heidelberg (KiTZ)
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
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
Stefan Hamelmann: Heidelberg University Hospital
Augusto Faria-Andrade: McGill University
Nada Jabado: McGill University
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)
Stefan M. Pfister: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Olaf Witt: Hopp Children’s Cancer Center Heidelberg (KiTZ)
David T. W. Jones: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Kornelius Kerl: University Children’s Hospital Münster
Till Milde: Hopp Children’s Cancer Center Heidelberg (KiTZ)

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40235-8

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