Identification of neoepitopes recognized by tumor-infiltrating lymphocytes (TILs) from patients with glioma

  • 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.

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Metadaten
Author:Davide Valentini, Martin Rao, Qingda Meng, Anna von Landenberg, Jiri Bartek, Georges Sinclair, Georgia Paraschoudi, Elke Jäger, Inti Harvey-Peredo, Ernest Dodoo, Markus Maeurer
URN:urn:nbn:de:hebis:30:3-486841
DOI:https://doi.org/10.18632/oncotarget.24955
ISSN:1949-2553
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/29731959
Parent Title (English):OncoTarget
Publisher:Impact Journals LLC
Place of publication:[s. l.]
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/04/13
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/01/17
Tag:Immunology; glioblastoma; immunotherapy; interferon gamma; neoepitopes; tumor-infiltrating lymphocytes
Volume:9
Issue:28
Page Number:12
First Page:19469
Last Page:19480
Note:
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
Note:
Correction erschienen in: OncoTarget, 9.2018, Nr. 95, S. 36817, doi:10.18632/oncotarget.26447
HeBIS-PPN:446275905
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0