Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy
| Autor: | Pierre-Yves Dietrich, Harpreet Singh-Jasuja, Jens Fritsche, Steffen Walter, Norbert Hilf, Judith Bucher, Katharina Dorsch, Christel Herold-Mende, Jennifer Lohr, Sylvia Flohr, Peter Lewandrowski, Stefan Stevanovic, Verona Vass, Paul R. Walker, Claudia Trautwein, Philipp Beckhove, Valérie Dutoit, Oliver Schoor, Toni Weinschenk, Hans-Georg Rammensee |
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| Rok vydání: | 2012 |
| Předmět: |
Antigens
CD31/metabolism Receptor-Like Protein Tyrosine Phosphatases Class 5/metabolism medicine.medical_treatment T cell Cell RNA Messenger/metabolism Antigens CD/metabolism Human leukocyte antigen CD8-Positive T-Lymphocytes Biology CD8-Positive T-Lymphocytes/immunology Mass Spectrometry Antigens Neoplasm/chemistry/immunology/therapeutic use Antigen Antigens CD Antigens Neoplasm Sequence Analysis Protein In vivo Glial Fibrillary Acidic Protein Glioblastoma/immunology/pathology/therapy medicine Humans RNA Messenger Oligonucleotide Array Sequence Analysis ddc:616 Antigen Presentation Antigen Presentation/physiology HLA-A Antigens Brain Neoplasms Receptor-Like Protein Tyrosine Phosphatases Class 5 Gene Expression Profiling Cytokines/metabolism Glial Fibrillary Acidic Protein/metabolism Immunotherapy Flow Cytometry Platelet Endothelial Cell Adhesion Molecule-1 medicine.anatomical_structure Immunology HLA-A Antigens/analysis/chemistry/immunology Peptides/analysis/immunology Cytokines Neurology (clinical) Glioblastoma Peptides CD8 Ex vivo Brain Neoplasms/immunology/pathology/therapy Chromatography Liquid |
| Zdroj: | Brain, Vol. 135, No Pt 4 (2012) pp. 1042-54 |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/aws042 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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