1. Neoepitope targets of tumour-infiltrating lymphocytes from patients with pancreatic cancer.
- Author
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Meng Q, Valentini D, Rao M, Moro CF, Paraschoudi G, Jäger E, Dodoo E, Rangelova E, Del Chiaro M, and Maeurer M
- Subjects
- Aquaporin 1 genetics, Aquaporin 1 immunology, Cell Line, Tumor, Cytotoxicity, Immunologic immunology, Flow Cytometry, Humans, Interferon-gamma immunology, Lymphocytes, Tumor-Infiltrating pathology, Pancreatic Neoplasms pathology, Epitopes immunology, Interferon-gamma genetics, Lymphocytes, Tumor-Infiltrating immunology, Pancreatic Neoplasms immunology
- Abstract
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 KRAS
G12v 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.- Published
- 2019
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