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The shared neoantigen landscape of MSI cancers reflects immunoediting during tumor evolution

Alexej Ballhausen, Moritz Jakob Przybilla, Michael Jendrusch, View ORCID ProfileSaskia Haupt, Elisabeth Pfaffendorf, Markus Draxlbauer, Florian Seidler, Sonja Krausert, Aysel Ahadova, Martin Simon Kalteis, Daniel Heid, Johannes Gebert, Maria Bonsack, Sarah Schott, Hendrik Bläker, Toni Seppälä, Jukka-Pekka Mecklin, Sanne Ten Broeke, Maartje Nielsen, Vincent Heuveline, Julia Krzykalla, Axel Benner, Angelika Beate Riemer, Magnus von Knebel Doeberitz, Matthias Kloor
doi: https://doi.org/10.1101/691469
Alexej Ballhausen
1Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
2Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL Heidelberg, Germany
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Moritz Jakob Przybilla
1Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
2Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL Heidelberg, Germany
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Michael Jendrusch
1Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
2Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL Heidelberg, Germany
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Saskia Haupt
4Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany
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  • ORCID record for Saskia Haupt
Elisabeth Pfaffendorf
1Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
2Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL Heidelberg, Germany
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Markus Draxlbauer
1Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
2Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL Heidelberg, Germany
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Florian Seidler
1Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
2Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL Heidelberg, Germany
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Sonja Krausert
1Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
2Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL Heidelberg, Germany
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Aysel Ahadova
1Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
2Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL Heidelberg, Germany
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Martin Simon Kalteis
1Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
2Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL Heidelberg, Germany
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Daniel Heid
1Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
2Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL Heidelberg, Germany
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Johannes Gebert
1Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
2Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL Heidelberg, Germany
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Maria Bonsack
5Immunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), Heidelberg, Germany
6Molecular Vaccine Design, German Center for Infection Research (DZIF), partner site Heidelberg, Heidelberg, Germany
7Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
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Sarah Schott
8Department of Obstetrics and Gynecology, University Hospital Heidelberg, Heidelberg, Germany
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Hendrik Bläker
9Institute of Pathology, University Hospital Leipzig, Leipzig, Germany
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Toni Seppälä
10Department of Gastrointestinal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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Jukka-Pekka Mecklin
11Department of Education and Research, Central Finland Central Hospital, Jyväskylä, Finland, and Sports and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
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Sanne Ten Broeke
12Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
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Maartje Nielsen
12Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
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Vincent Heuveline
4Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany
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Julia Krzykalla
13Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Axel Benner
13Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Angelika Beate Riemer
5Immunotherapy and Immunoprevention, German Cancer Research Center (DKFZ), Heidelberg, Germany
6Molecular Vaccine Design, German Center for Infection Research (DZIF), partner site Heidelberg, Heidelberg, Germany
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Magnus von Knebel Doeberitz
1Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
2Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL Heidelberg, Germany
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Matthias Kloor
1Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
2Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
3Molecular Medicine Partnership Unit (MMPU), Heidelberg University Hospital and EMBL Heidelberg, Germany
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  • For correspondence: matthias.kloor@med.uni-heidelberg.de
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Abstract

The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are particularly abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. The abundance of mutational neoantigens renders MSI cancers sensitive to immune checkpoint blockade. However, the neoantigen landscape of MMR-deficient cancers has not yet been systematically mapped. In the present study, we used a novel tool to monitor neoantigen-inducing indel mutations in MSI colorectal and endometrial cancer. Our results show that MSI cancers share several highly immunogenic neoantigens that result from specific, recurrent indel mutation events. Notably, the frequency of such indel mutations was negatively correlated to the predicted immunogenicity of the resulting neoantigens. These observations suggest continuous immunoediting of emerging MMR-deficient cells during tumor evolution.

One sentence summary Quantitative indel mutation analysis reveals evidence of immune selection in mismatch repair-deficient cancers

Footnotes

  • ↵$ shared first authorship

  • https://github.com/atb-data/neoantigen-landscape-msi

  • Glossary

    ELS
    Epitope likelihood score
    GELS
    General epitope likelihood score
    IRS
    Immune relevance score, based on the mutation frequency (ReFrame) and the GELS
    M1
    Reading frame resulting from the deletion of one nucleotide or insertions of two nucleotides
    M2
    Reading frame resulting from the deletions of two nucleotides or insertion of one nucleotide
    m1, m2, m3, etc.
    Minus one, two, three base pair deletions
    p1, p2, p3, etc.
    Plus one, two, three base pair insertions
    ReFrame
    REgression-based FRAMEshift quantification
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    The shared neoantigen landscape of MSI cancers reflects immunoediting during tumor evolution
    Alexej Ballhausen, Moritz Jakob Przybilla, Michael Jendrusch, Saskia Haupt, Elisabeth Pfaffendorf, Markus Draxlbauer, Florian Seidler, Sonja Krausert, Aysel Ahadova, Martin Simon Kalteis, Daniel Heid, Johannes Gebert, Maria Bonsack, Sarah Schott, Hendrik Bläker, Toni Seppälä, Jukka-Pekka Mecklin, Sanne Ten Broeke, Maartje Nielsen, Vincent Heuveline, Julia Krzykalla, Axel Benner, Angelika Beate Riemer, Magnus von Knebel Doeberitz, Matthias Kloor
    bioRxiv 691469; doi: https://doi.org/10.1101/691469
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    The shared neoantigen landscape of MSI cancers reflects immunoediting during tumor evolution
    Alexej Ballhausen, Moritz Jakob Przybilla, Michael Jendrusch, Saskia Haupt, Elisabeth Pfaffendorf, Markus Draxlbauer, Florian Seidler, Sonja Krausert, Aysel Ahadova, Martin Simon Kalteis, Daniel Heid, Johannes Gebert, Maria Bonsack, Sarah Schott, Hendrik Bläker, Toni Seppälä, Jukka-Pekka Mecklin, Sanne Ten Broeke, Maartje Nielsen, Vincent Heuveline, Julia Krzykalla, Axel Benner, Angelika Beate Riemer, Magnus von Knebel Doeberitz, Matthias Kloor
    bioRxiv 691469; doi: https://doi.org/10.1101/691469

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