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.
| Errataetall: |
ErratumIn: Oncotarget. 2018 Dec 4;9(95):36817. - PMID 30613370 |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2018 |
|---|---|
| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
|---|---|
| Enthalten in: |
Oncotarget - 9(2018), 28 vom: 13. Apr., Seite 19469-19480 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Valentini, Davide [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Glioblastoma |
|---|
| Anmerkungen: |
Date Revised 20.11.2019 published: Electronic-eCollection ErratumIn: Oncotarget. 2018 Dec 4;9(95):36817. - PMID 30613370 Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.18632/oncotarget.24955 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM283790261 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM283790261 | ||
| 003 | DE-627 | ||
| 005 | 20231225041718.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2018 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.18632/oncotarget.24955 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0945.xml |
| 035 | |a (DE-627)NLM283790261 | ||
| 035 | |a (NLM)29731959 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Valentini, Davide |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Identification of neoepitopes recognized by tumor-infiltrating lymphocytes (TILs) from patients with glioma |
| 264 | 1 | |c 2018 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 20.11.2019 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a ErratumIn: Oncotarget. 2018 Dec 4;9(95):36817. - PMID 30613370 | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Immunology | |
| 650 | 4 | |a glioblastoma | |
| 650 | 4 | |a immunotherapy | |
| 650 | 4 | |a interferon gamma | |
| 650 | 4 | |a neoepitopes | |
| 650 | 4 | |a tumor-infiltrating lymphocytes | |
| 700 | 1 | |a Rao, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Meng, Qingda |e verfasserin |4 aut | |
| 700 | 1 | |a von Landenberg, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Bartek, Jiri |c Jr |e verfasserin |4 aut | |
| 700 | 1 | |a Sinclair, Georges |e verfasserin |4 aut | |
| 700 | 1 | |a Paraschoudi, Georgia |e verfasserin |4 aut | |
| 700 | 1 | |a Jäger, Elke |e verfasserin |4 aut | |
| 700 | 1 | |a Harvey-Peredo, Inti |e verfasserin |4 aut | |
| 700 | 1 | |a Dodoo, Ernest |e verfasserin |4 aut | |
| 700 | 1 | |a Maeurer, Markus |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Oncotarget |d 2010 |g 9(2018), 28 vom: 13. Apr., Seite 19469-19480 |w (DE-627)NLM199620113 |x 1949-2553 |7 nnns |
| 773 | 1 | 8 | |g volume:9 |g year:2018 |g number:28 |g day:13 |g month:04 |g pages:19469-19480 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.18632/oncotarget.24955 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 9 |j 2018 |e 28 |b 13 |c 04 |h 19469-19480 | ||