Abstract
Peptides presented at the cell surface reflect the protein content of the cell; those on HLA class I molecules comprise the critical peptidome elements interacting with CD8 T lymphocytes. We hypothesize that peptidomes from ex vivo tumour samples encompass immunogenic tumour antigens. Here, we uncover >6000 HLA-bound peptides from HLA-A*02(+) glioblastoma, of which over 3000 were restricted by HLA-A*02. We prioritized in-depth investigation of 10 glioblastoma-associated antigens based on high expression in tumours, very low or absent expression in healthy tissues, implication in gliomagenesis and immunogenicity. Patients with glioblastoma showed no T cell tolerance to these peptides. Moreover, we demonstrated specific lysis of tumour cells by patients' CD8(+) T cells in vitro. In vivo, glioblastoma-specific CD8(+) T cells were present at the tumour site. Overall, our data show the physiological relevance of the peptidome approach and provide a critical advance for designing a rational glioblastoma immunotherapy. The peptides identified in our study are currently being tested as a multipeptide vaccine (IMA950) in patients with glioblastoma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigen Presentation / physiology
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Antigens, CD / metabolism
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Antigens, Neoplasm / chemistry
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Antigens, Neoplasm / immunology*
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Antigens, Neoplasm / therapeutic use
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Brain Neoplasms / immunology*
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Brain Neoplasms / pathology
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Brain Neoplasms / therapy
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CD8-Positive T-Lymphocytes / immunology
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Chromatography, Liquid
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Cytokines / metabolism
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Flow Cytometry
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Gene Expression Profiling
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Glial Fibrillary Acidic Protein / metabolism
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Glioblastoma / immunology*
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Glioblastoma / pathology
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Glioblastoma / therapy
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HLA-A Antigens / analysis
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HLA-A Antigens / chemistry
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HLA-A Antigens / immunology
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Humans
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Mass Spectrometry
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Oligonucleotide Array Sequence Analysis
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Peptides / analysis
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Peptides / immunology*
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Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
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RNA, Messenger / metabolism
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Receptor-Like Protein Tyrosine Phosphatases, Class 5 / metabolism
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Sequence Analysis, Protein
Substances
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Antigens, CD
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Antigens, Neoplasm
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Cytokines
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Glial Fibrillary Acidic Protein
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HLA-A Antigens
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Peptides
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Platelet Endothelial Cell Adhesion Molecule-1
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RNA, Messenger
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PTPRZ1 protein, human
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Receptor-Like Protein Tyrosine Phosphatases, Class 5