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Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy

Herold-Mende, Christel
Hilf, Norbert
Schoor, Oliver
Beckhove, Philipp
Bucher, Judith
Dorsch, Katharina
Flohr, Sylvia
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Published in Brain. 2012, vol. 135, no. Pt 4, p. 1042-54
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.
Keywords Antigen Presentation/physiologyAntigens, CD/metabolismAntigens, CD31/metabolismAntigens, Neoplasm/chemistry/immunology/therapeutic useBrain Neoplasms/immunology/pathology/therapyCD8-Positive T-Lymphocytes/immunologyChromatography, LiquidCytokines/metabolismFlow CytometryGene Expression ProfilingGlial Fibrillary Acidic Protein/metabolismGlioblastoma/immunology/pathology/therapyHLA-A Antigens/analysis/chemistry/immunologyHumansMass SpectrometryOligonucleotide Array Sequence AnalysisPeptides/analysis/immunologyRNA, Messenger/metabolismReceptor-Like Protein Tyrosine Phosphatases, Class 5/metabolismSequence Analysis, Protein
PMID: 22418738
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Article (Published version) (899 Kb) - public document Free access
Research groups Immunobiologie des tumeurs du cerveau (669)
Immunothérapie des cancers (42)
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DUTOIT VALLOTTON, Valérie et al. Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy. In: Brain, 2012, vol. 135, n° Pt 4, p. 1042-54. doi: 10.1093/brain/aws042 https://archive-ouverte.unige.ch/unige:43340

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Deposited on : 2014-12-15

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