CIITA-transduced glioblastoma cells uncover a rich repertoire of clinically relevant tumor-associated HLA-II antigens
| Autor: | Michal Bassani-Sternberg, Elise Ramia, Brian Stevenson, Greta Forlani, Elodie Lauret Marie Joseph, Michael Linnebacher, Roberto S. Accolla, Florian Huber, HuiSong Pak, Justine Michaux |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Antigen discovery
CIITA Cancer Biology Cancer therapeutics Glioblastoma HLA class II Immunology Immunopeptidomics Mass Spectrometry Tumor antigens HLA-II human leukocyte antigen class II Biochemistry Epitope WES whole-exome sequencing Analytical Chemistry APCs antigen presenting cells 0303 health sciences biology Brain Neoplasms 030302 biochemistry & molecular biology a.u. arbitrary units Nuclear Proteins TH T helper cells 3. Good health TAAs tumor-associated antigens medicine.anatomical_structure SNPs single nucleotide polymorphisms PSM peptide spectrum match HLA-I human leukocyte antigen class I FDR false discovery rate T cell Class II major histocompatibility complex transactivator Human leukocyte antigen Major histocompatibility complex TcR T cell receptors IFNγ Interferon gamma ER endoplasmic reticulum 03 medical and health sciences Antigen Special Issue: Immunopeptidomics ERAAP ER aminopeptidase-associated with antigen processing Antigens Neoplasm Cell Line Tumor medicine MHC major histocompatibility complex Animals Humans Antigen-presenting cell Molecular Biology 030304 developmental biology PBMCs peripheral blood mononuclear cells HLA human leukocyte antigen Research T-cell receptor Histocompatibility Antigens Class II LFQ label-free quantification TAP transporter-associated with antigen processing CTL cytotoxic T cells CIITA class II major histocompatibility complex transactivator HCD higher-energy collision dissociation biology.protein Cancer research Trans-Activators Antigens Neoplasm/immunology Brain Neoplasms/immunology Cattle Glioblastoma/immunology Histocompatibility Antigens Class II/immunology Nuclear Proteins/genetics Nuclear Proteins/immunology Peptides/immunology Trans-Activators/genetics Trans-Activators/immunology GBM glioblastoma Peptides SNVs single nucleotide variants |
| Zdroj: | Molecular & Cellular Proteomics : MCP Molecular & cellular proteomics, vol. 20, pp. 100032 |
| Popis: | CD4+ T cell responses are crucial for inducing and maintaining effective anticancer immunity, and the identification of human leukocyte antigen class II (HLA-II) cancer-specific epitopes is key to the development of potent cancer immunotherapies. In many tumor types, and especially in glioblastoma (GBM), HLA-II complexes are hardly ever naturally expressed. Hence, little is known about immunogenic HLA-II epitopes in GBM. With stable expression of the class II major histocompatibility complex transactivator (CIITA) coupled to a detailed and sensitive mass spectrometry–based immunopeptidomics analysis, we here uncovered a remarkable breadth of the HLA-ligandome in HROG02, HROG17, and RA GBM cell lines. The effect of CIITA expression on the induction of the HLA-II presentation machinery was striking in each of the three cell lines, and it was significantly higher compared with interferon gamma (IFNɣ) treatment. In total, we identified 16,123 unique HLA-I peptides and 32,690 unique HLA-II peptides. In order to genuinely define the identified peptides as true HLA ligands, we carefully characterized their association with the different HLA allotypes. In addition, we identified 138 and 279 HLA-I and HLA-II ligands, respectively, most of which are novel in GBM, derived from known GBM-associated tumor antigens that have been used as source proteins for a variety of GBM vaccines. Our data further indicate that CIITA-expressing GBM cells acquired an antigen presenting cell-like phenotype as we found that they directly present external proteins as HLA-II ligands. Not only that CIITA-expressing GBM cells are attractive models for antigen discovery endeavors, but also such engineered cells have great therapeutic potential through massive presentation of a diverse antigenic repertoire. Graphical Abstract Highlights • CIITA-expressing glioblastoma cells express high levels of HLA-II complexes. • CIITA induces peptide presentation across the HLA-DP, -DQ, and -DR allotypes. • Many clinically relevant glioblastoma-associated tumor antigens were detected. • Such cells may have great therapeutic potential in clinical settings. In Brief CD4+ T cell responses are crucial for inducing and maintaining effective anticancer immunity; however, in glioblastoma and many solid tumors, HLA-II complexes are hardly ever naturally expressed. Hence, little is known about immunogenic HLA-II epitopes in glioblastoma. With stable expression of the class II major histocompatibility complex transactivator (CIITA) coupled to a detailed immunopeptidomics, we uncovered a remarkable breadth of the HLA-ligandome in three glioblastoma cell lines and identified many cancer-associated ligands with implications for the development of cancer immunotherapies. |
| Databáze: | OpenAIRE |
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