TY  - JOUR
A1  - Valentini, Davide
A1  - Rao, Martin
A1  - Meng, Qingda
A1  - Landenberg, Anna von
A1  - Bartek, Jiri
A1  - Sinclair, Georges
A1  - Paraschoudi, Georgia
A1  - Jäger, Elke
A1  - Harvey-Peredo, Inti
A1  - Dodoo, Ernest
A1  - Maeurer, Markus
T1  - Identification of neoepitopes recognized by tumor-infiltrating lymphocytes (TILs) from patients with glioma
T2  - OncoTarget
N2  - 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.
KW  - tumor-infiltrating lymphocytes
KW  - immunotherapy
KW  - neoepitopes
KW  - glioblastoma
KW  - interferon gamma
KW  - Immunology
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/48684
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-486841
SN  - 1949-2553
N1  - All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
N1  - Correction erschienen in: OncoTarget, 9.2018, Nr. 95, S. 36817, doi:10.18632/oncotarget.26447
VL  - 9
IS  - 28
SP  - 19469
EP  - 19480
PB  - Impact Journals LLC
CY  - [s. l.]
ER  -