title: Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy.
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.
authors.affiliation: Laboratory of Tumour Immunology, Centre of Oncology, Geneva University Hospital, 1211 Geneva 14, Switzerland.
authors.forename: Valérie
authors.initials: V
authors.lastname: Dutoit
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.forename: Norbert
authors.initials: N
authors.lastname: Hilf
authors.forename: Oliver
authors.initials: O
authors.lastname: Schoor
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
authors.forename: Judith
authors.initials: J
authors.lastname: Bucher
authors.forename: Katharina
authors.initials: K
authors.lastname: Dorsch
authors.forename: Sylvia
authors.initials: S
authors.lastname: Flohr
authors.forename: Jens
authors.initials: J
authors.lastname: Fritsche
authors.forename: Peter
authors.initials: P
authors.lastname: Lewandrowski
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lohr
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Rammensee
authors.forename: Stefan
authors.initials: S
authors.lastname: Stevanovic
authors.forename: Claudia
authors.initials: C
authors.lastname: Trautwein
authors.forename: Verona
authors.initials: V
authors.lastname: Vass
authors.forename: Steffen
authors.initials: S
authors.lastname: Walter
authors.forename: Paul R
authors.initials: PR
authors.lastname: Walker
authors.forename: Toni
authors.initials: T
authors.lastname: Weinschenk
authors.forename: Harpreet
authors.initials: H
authors.lastname: Singh-Jasuja
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Dietrich
mesh_terms: D017951:Antigen Presentation / Q000502:physiology; D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002853:Chromatography, Liquid; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005909:Glioblastoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D015234:HLA-A Antigens / Q000032:analysis / Q000737:chemistry / Q000276:immunology; D006801:Humans; D013058:Mass Spectrometry; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000032:analysis / Q000276:immunology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000378:metabolism; D020539:Sequence Analysis, Protein
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D015234:HLA-A Antigens; D010455:Peptides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; C516895:PTPRZ1 protein, human; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5