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The natural HLA ligandome of glioblastoma stem-like cells: antigen discovery for T cell-based immunotherapy

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Abstract

Glioblastoma is the most frequent malignant primary brain tumor. In a hierarchical tumor model, glioblastoma stem-like cells (GSC) play a major role in tumor initiation and maintenance as well as in therapy resistance and recurrence. Thus, targeting this cellular subset may be key to effective immunotherapy. Here, we present a mass spectrometry-based analysis of HLA-presented peptidomes of GSC and glioblastoma patient specimens. Based on the analysis of patient samples (n = 9) and GSC (n = 3), we performed comparative HLA peptidome profiling against a dataset of normal human tissues. Using this immunopeptidome-centric approach we could clearly delineate a subset of naturally presented, GSC-associated HLA ligands, which might serve as highly specific targets for T cell-based immunotherapy. In total, we identified 17 antigens represented by 41 different HLA ligands showing natural and exclusive presentation both on GSC and patient samples. Importantly, in vitro immunogenicity and antigen-specific target cell killing assays suggest these peptides to be epitopes of functional CD8+ T cell responses, thus rendering them prime candidates for antigen-specific immunotherapy of glioblastoma.

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Funding

This project was funded by a grant of the Canton of Zurich (HSM-2) to LR, PR and MiW. MN received financial support from the Filling-The-Gap Program (University of Zurich), the Hartmann Müller-Foundation and the EMDO Foundation. HGR received financial support from the ERC Grant 339842, MUTAEDITING.

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Authors and Affiliations

  1. Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, Frauenklinikstrasse 10, 8091, Zurich, Switzerland

    Marian Christoph Neidert, Sophie Shih-Yüng Wang & Luca Regli

  2. Department of Immunology, Institute for Cell Biology, University of Tübingen, Auf der Morgenstelle 15, 72076, Tübingen, Germany

    Daniel Johannes Kowalewski, Linus Backert, Lena Katharina Freudenmann, Janet Kerstin Peper, Ana Marcu, Juliane Sarah Walz, Hans-Georg Rammensee & Stefan Stevanović

  3. Laboratory of Molecular Neuro-Oncology, Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland

    Marian Christoph Neidert, Manuela Silginer, Konstantina Kapolou, Sophie Shih-Yüng Wang, Fabian Wolpert, Patrick Roth, Michael Weller & Günter Eisele

  4. Applied Bioinformatics, Center of Bioinformatics and Department of Computer Science, University of Tübingen, Sand 14, 72076, Tübingen, Germany

    Linus Backert

  5. DKFZ Partner Site Tübingen, German Cancer Consortium (DKTK), Auf der Morgenstelle 15, 72076, Tübingen, Germany

    Lena Katharina Freudenmann, Hans-Georg Rammensee & Stefan Stevanović

  6. Department of Hematology and Oncology, University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany

    Juliane Sarah Walz

  7. Swiss Red Cross Blood Transfusion Services Zurich and Chur, Rütistrasse 19, 8952, Zurich, Switzerland

    Reinhard Henschler

  8. Swiss Red Cross Blood Transfusion Services Zurich and Chur, Loestrasse 170, 7000, Chur, Switzerland

    Reinhard Henschler

  9. Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

    Katrin Lamszus & Manfred Westphal

Authors
  1. Marian Christoph Neidert
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  2. Daniel Johannes Kowalewski
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  3. Manuela Silginer
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  4. Konstantina Kapolou
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  5. Linus Backert
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  8. Ana Marcu
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  9. Sophie Shih-Yüng Wang
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  10. Juliane Sarah Walz
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  11. Fabian Wolpert
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  12. Hans-Georg Rammensee
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  13. Reinhard Henschler
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  14. Katrin Lamszus
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  15. Manfred Westphal
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  16. Patrick Roth
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  17. Luca Regli
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  18. Stefan Stevanović
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  19. Michael Weller
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  20. Günter Eisele
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Corresponding author

Correspondence to Marian Christoph Neidert.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Conflict of interest

DK is an employee and HGR is a shareholder of Immatics Biotechnologies GmbH. HGR is also shareholder of Curevac AG. MiW has received research grants from Acceleron, Actelion, Bayer, Isarna, MSD, Merck & Co, Novocure, Piqur and Roche and honoraria for lectures or advisory board participation or consulting from BMS, Celldex, Immunocellular Therapeutics, Isarna, Magforce, MSD, Merck & Co, Northwest Biotherapeutics, Novocure, Pfizer, Roche, Teva and Tocagen. FW has received travel support from Roche. PR has received honoraria from Roche, MSD, Novocure, Novartis and BMS for advisory board participation or lectures. The other authors declare no competing financial interests.

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Neidert, M.C., Kowalewski, D.J., Silginer, M. et al. The natural HLA ligandome of glioblastoma stem-like cells: antigen discovery for T cell-based immunotherapy. Acta Neuropathol 135, 923–938 (2018). https://doi.org/10.1007/s00401-018-1836-9

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  • DOI: https://doi.org/10.1007/s00401-018-1836-9

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