Neoepitope targets of tumour-infiltrating lymphocytes from patients with pancreatic cancer
BACKGROUND: Pancreatic cancer exhibits a poor prognosis and often presents with metastasis at diagnosis. Immunotherapeutic approaches targeting private cancer mutations (neoantigens) are a clinically viable option to improve clinical outcomes.
METHODS: 3/40 TIL lines (PanTT26, PanTT39, PanTT77) were more closely examined for neoantigen recognition. Whole-exome sequencing was performed to identify non-synonymous somatic mutations. Mutant peptides were synthesised and assessed for antigen-specific IFN-γ production and specific tumour killing in a standard Cr51 assay. TIL phenotype was tested by flow cytometry. Lymphocytes and HLA molecules in tumour tissue were visualised by immunohistochemistry.
RESULTS: PanTT26 and PanTT39 TILs recognised and killed the autologous tumour cells. PanTT26 TIL recognised the KRASG12v mutation, while a PanTT39 CD4+ TIL clone recognised the neoepitope (GLLRYWRTERLF) from an aquaporin 1-like protein (gene: K7N7A8). Repeated stimulation of TILs with the autologous tumour cells line lead to focused recognition of several mutated targets, based on IFN-γ production. TILs and corresponding PBMCs from PanTT77 showed shared as well as mutually exclusively tumour epitope recognition (TIL-responsive or PBMC-responsive).
CONCLUSION: This study provides methods to robustly screen T-cell targets for pancreatic cancer. Pancreatic cancer is immunogenic and immunotherapeutic approaches can be used to develop improved, targeted therapies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:120 |
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| Enthalten in: |
British journal of cancer - 120(2019), 1 vom: 30. Jan., Seite 97-108 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Meng, Qingda [VerfasserIn] |
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| Links: |
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| Themen: |
146410-94-8 |
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| Anmerkungen: |
Date Completed 18.09.2019 Date Revised 09.01.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41416-018-0262-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM290109647 |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: Pancreatic cancer exhibits a poor prognosis and often presents with metastasis at diagnosis. Immunotherapeutic approaches targeting private cancer mutations (neoantigens) are a clinically viable option to improve clinical outcomes | ||
| 520 | |a METHODS: 3/40 TIL lines (PanTT26, PanTT39, PanTT77) were more closely examined for neoantigen recognition. Whole-exome sequencing was performed to identify non-synonymous somatic mutations. Mutant peptides were synthesised and assessed for antigen-specific IFN-γ production and specific tumour killing in a standard Cr51 assay. TIL phenotype was tested by flow cytometry. Lymphocytes and HLA molecules in tumour tissue were visualised by immunohistochemistry | ||
| 520 | |a RESULTS: PanTT26 and PanTT39 TILs recognised and killed the autologous tumour cells. PanTT26 TIL recognised the KRASG12v mutation, while a PanTT39 CD4+ TIL clone recognised the neoepitope (GLLRYWRTERLF) from an aquaporin 1-like protein (gene: K7N7A8). Repeated stimulation of TILs with the autologous tumour cells line lead to focused recognition of several mutated targets, based on IFN-γ production. TILs and corresponding PBMCs from PanTT77 showed shared as well as mutually exclusively tumour epitope recognition (TIL-responsive or PBMC-responsive) | ||
| 520 | |a CONCLUSION: This study provides methods to robustly screen T-cell targets for pancreatic cancer. Pancreatic cancer is immunogenic and immunotherapeutic approaches can be used to develop improved, targeted therapies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Valentini, Davide |e verfasserin |4 aut | |
| 700 | 1 | |a Rao, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Moro, Carlos Fernández |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 Dodoo, Ernest |e verfasserin |4 aut | |
| 700 | 1 | |a Rangelova, Elena |e verfasserin |4 aut | |
| 700 | 1 | |a Del Chiaro, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Maeurer, Markus |e verfasserin |4 aut | |
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