Davide Valentini, Martin Rao, Qingda Meng, Anna von Landenberg, Jiri Bartek, Georges Sinclair, Georgia Paraschoudi, Elke Jäger, Inti Harvey-Peredo, Ernest Dodoo, Markus Maeurer
- Neoepitope-specific T-cell responses have been shown to induce durable clinical responses in patients with advanced cancers. We explored the recognition patterns of tumor-infiltrating T lymphocytes (TILs) from patients with glioblastoma multiforme (GBM), the most fatal form of tumors of the central nervous system. Whole-genome sequencing was used for generating DNA sequences representing the entire spectrum of ‘private’ somatic mutations in GBM tumors from five patients, followed by 15-mer peptide prediction and subsequent peptide synthesis. For each mutated peptide sequence, the wildtype sequence was also synthesized and individually co-cultured with autologous GBM TILs, which had been expanded in vitro with a combination of interleukin (IL)-2, IL-15 and IL-21. After seven days of culture, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α) and/or IL-17A production was measured by ELISA in culture supernatants, and used as an epitope-specific immune response readout. Mutated peptides that induced a strong cytokine response were considered to contain legitimate neoepitopes. TILs from 5/5 patients with GBM exhibited specific immune reactivity profiles to the nominal target peptides, defined by IFN-γ and/or TNF-α production, as well as IL-17A. Neoepitopes, defined by mutated peptides inducing IFN-γ and/or TNF-α production without or only minimal reactivity to the wildtype sequences, were found for each individual patient. CD8+ TILs dominated the patients’ responses to private neoepitopes. The present study shows that neoepitope-specific TIL reactivity constitutes an important arm of anti-tumor immune responses in patients with GBM, and thus a powerful tool for developing next-generation personalized immunotherapies.
MetadatenAuthor: | Davide Valentini, Martin Rao, Qingda Meng, Anna von LandenbergGND, Jiri Bartek, Georges Sinclair, Georgia Paraschoudi, Elke Jäger, Inti Harvey-Peredo, Ernest Dodoo, Markus Maeurer |
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URN: | urn:nbn:de:hebis:30:3-486841 |
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DOI: | https://doi.org/10.18632/oncotarget.24955 |
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ISSN: | 1949-2553 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/29731959 |
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Parent Title (English): | OncoTarget |
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Publisher: | Impact Journals LLC |
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Place of publication: | [s. l.] |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2018 |
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Date of first Publication: | 2018/04/13 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2019/01/17 |
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Tag: | Immunology; glioblastoma; immunotherapy; interferon gamma; neoepitopes; tumor-infiltrating lymphocytes |
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Volume: | 9 |
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Issue: | 28 |
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Page Number: | 12 |
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First Page: | 19469 |
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Last Page: | 19480 |
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Note: | All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License. |
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Note: | Correction erschienen in: OncoTarget, 9.2018, Nr. 95, S. 36817, doi:10.18632/oncotarget.26447 |
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HeBIS-PPN: | 446275905 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 3.0 |
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