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      The SysteMHC Atlas project

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      Nucleic Acids Research
      Oxford University Press

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          Abstract

          Mass spectrometry (MS)-based immunopeptidomics investigates the repertoire of peptides presented at the cell surface by major histocompatibility complex (MHC) molecules. The broad clinical relevance of MHC-associated peptides, e.g. in precision medicine, provides a strong rationale for the large-scale generation of immunopeptidomic datasets and recent developments in MS-based peptide analysis technologies now support the generation of the required data. Importantly, the availability of diverse immunopeptidomic datasets has resulted in an increasing need to standardize, store and exchange this type of data to enable better collaborations among researchers, to advance the field more efficiently and to establish quality measures required for the meaningful comparison of datasets. Here we present the SysteMHC Atlas ( https://systemhcatlas.org), a public database that aims at collecting, organizing, sharing, visualizing and exploring immunopeptidomic data generated by MS. The Atlas includes raw mass spectrometer output files collected from several laboratories around the globe, a catalog of context-specific datasets of MHC class I and class II peptides, standardized MHC allele-specific peptide spectral libraries consisting of consensus spectra calculated from repeat measurements of the same peptide sequence, and links to other proteomics and immunology databases. The SysteMHC Atlas project was created and will be further expanded using a uniform and open computational pipeline that controls the quality of peptide identifications and peptide annotations. Thus, the SysteMHC Atlas disseminates quality controlled immunopeptidomic information to the public domain and serves as a community resource toward the generation of a high-quality comprehensive map of the human immunopeptidome and the support of consistent measurement of immunopeptidomic sample cohorts.

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          Most cited references43

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            The immune epitope database (IEDB) 3.0

            The IEDB, www.iedb.org, contains information on immune epitopes—the molecular targets of adaptive immune responses—curated from the published literature and submitted by National Institutes of Health funded epitope discovery efforts. From 2004 to 2012 the IEDB curation of journal articles published since 1960 has caught up to the present day, with >95% of relevant published literature manually curated amounting to more than 15 000 journal articles and more than 704 000 experiments to date. The revised curation target since 2012 has been to make recent research findings quickly available in the IEDB and thereby ensure that it continues to be an up-to-date resource. Having gathered a comprehensive dataset in the IEDB, a complete redesign of the query and reporting interface has been performed in the IEDB 3.0 release to improve how end users can access this information in an intuitive and biologically accurate manner. We here present this most recent release of the IEDB and describe the user testing procedures as well as the use of external ontologies that have enabled it.
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              Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry

              Although mutations may represent attractive targets for immunotherapy, direct identification of mutated peptide ligands isolated from human leucocyte antigens (HLA) on the surface of native tumour tissue has so far not been successful. Using advanced mass spectrometry (MS) analysis, we survey the melanoma-associated immunopeptidome to a depth of 95,500 patient-presented peptides. We thereby discover a large spectrum of attractive target antigen candidates including cancer testis antigens and phosphopeptides. Most importantly, we identify peptide ligands presented on native tumour tissue samples harbouring somatic mutations. Four of eleven mutated ligands prove to be immunogenic by neoantigen-specific T-cell responses. Moreover, tumour-reactive T cells with specificity for selected neoantigens identified by MS are detected in the patient's tumour and peripheral blood. We conclude that direct identification of mutated peptide ligands from primary tumour material by MS is possible and yields true neoepitopes with high relevance for immunotherapeutic strategies in cancer.
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                Author and article information

                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                04 January 2018
                29 July 2017
                29 July 2017
                : 46
                : Database issue , Database issue
                : D1237-D1247
                Affiliations
                Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland
                Functional Genomics Center Zurich, ETH Zurich and University of Zurich, Zurich 8057, Switzerland
                Scientific IT Services (SIS), ETH Zurich, Zurich 8093, Switzerland
                European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
                Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, H3T 1J4, Canada
                Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, 72076, Germany
                German Cancer Consortium (DKTK), DKFZ partner site Tübingen, Tübingen, 72076, Germany
                Ludwig Institute for Cancer Research, University Hospital of Lausanne, Lausanne 1011, Switzerland
                Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH, The Netherlands
                Netherlands Proteomics Centre, Utrecht, 3584 CH, The Netherlands
                La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
                Department of Infectious Diseases, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands
                Department of Immunology, Max Planck Institute for Infection Biology, Berlin 10117, Germany
                Vaccine Research and Translational Medicine, Agenus Switzerland Inc., 4157 Basel, Switzerland
                Department of Pathology, BRCF Metabolomics Core, University of Michigan, Ann Arbor, MI 48109, USA
                Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
                Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín, Buenos Aires, 1650, Argentina
                Department of Bio and Health Informatics, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark
                Institute for Systems Biology, Seattle, WA 98109, USA
                Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SE-171 77, Sweden
                Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, SE-171 77, Sweden
                Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton 3800, Australia
                Proteomics Unit, Spanish National Biotechnology Centre, Madrid 28049, Spain
                Center for Biomedical Mass Spectrometry, Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA
                The Jenner Institute, Target Discovery Institute Mass Spectrometry Laboratory, University of Oxford, Oxford, OX3 7FZ, UK
                Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands
                Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, 3720 BA, The Netherlands
                Centre for Immune Regulation, Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo 0372, Norway
                The Brain Institute, Universidade Federal do Rio Grande do Norte, 59056–450, Natal-RN, Brazil
                Department of Biology, Technion, Israel Institute of Technology, Haifa 3200003, Israel
                Faculty of Science, University of Zurich, 8006 Zurich, Switzerland
                Author notes
                To whom correspondence should be addressed. Tel: +41 44 633 26 97; Fax: +41 44 633 10 51; Email: caron@ 123456imsb.biol.ethz.ch . Correspondence may also be addressed to Ruedi Aebersold. Tel: +41 44 633 31 70; Fax: +41 44 633 10 51; Email: aebersold@ 123456imsb.biol.ethz.ch

                These authors contributed equally to the paper as first authors.

                Author information
                http://orcid.org/0000-0002-3905-4335
                http://orcid.org/0000-0002-2405-4404
                Article
                gkx664
                10.1093/nar/gkx664
                5753376
                28985418
                4c8d8821-a9fa-4d43-a10a-671f5d615937
                © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                History
                : 21 July 2017
                : 16 July 2017
                : 13 June 2017
                Page count
                Pages: 11
                Categories
                Database Issue

                Genetics
                Genetics

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