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Moreno Di Marco, Janet Kerstin Peper, Hans-Georg Rammensee
The interrogation of cell surface-presented immunogenic epitopes is of great importance to differentiate diseased cells in consequence to malignant transformation or viral infections. On the basis of this knowledge, next-generation immunotherapies against cancers, autoimmunity, or infectious diseases can be developed. The identification of altered peptide repertoires of transformed cells renders mass spectrometry-based analysis indispensable. This is evident considering the low correlation of gene or protein expression alterations, respectively, with changes in the peptide repertoire rendering those analyses less informative...
March 2017: Cancer Journal
Tuula A Nyman, Martina B Lorey, Wojciech Cypryk, Sampsa Matikainen
The immune system is our defense system against microbial infections and tissue injury, and understanding how it works in detail is essential for developing drugs for different diseases. Mass spectrometry-based proteomics can provide in-depth information on the molecular mechanisms involved in immune responses. Areas covered: Summarized are the key immunology findings obtained with MS-based proteomics in the past five years, with a focus on inflammasome activation, global protein secretion, mucosal immunology, immunopeptidome and T cells...
April 13, 2017: Expert Review of Proteomics
Haley L Peters, Satyendra C Tripathi, Celine Kerros, Hiroyuki Katayama, Haven R Garber, Lisa S St John, Lorenzo Federico, Ismail M Meraz, Jack A Roth, Boris Sepesi, Mourad Majidi, Kathryn Ruisaard, Karen Clise-Dwyer, Jason Roszik, Don L Gibbons, John V Heymach, Stephen G Swisher, Chantale Bernatchez, Gheath Alatrash, Samir Hanash, Jeffrey J Molldrem
Immunotherapies targeting immune checkpoints have proven efficacious in reducing the burden of lung cancer in patients; however, the antigenic targets of these reinvigorated T cells remain poorly defined. Lung cancer tumors contain tumor-associated macrophages (TAM) and neutrophils, which release the serine proteases neutrophil elastase (NE) and proteinase 3 (P3) into the tumor microenvironment. NE and P3 shape the antitumor adaptive immune response in breast cancer and melanoma. In this report, we demonstrate that lung cancer cells cross-presented the tumor-associated antigen PR1, derived from NE and P3...
April 2017: Cancer Immunology Research
Phillip Pymm, Patricia T Illing, Sri H Ramarathinam, Geraldine M O'Connor, Victoria A Hughes, Corinne Hitchen, David A Price, Bosco K Ho, Daniel W McVicar, Andrew G Brooks, Anthony W Purcell, Jamie Rossjohn, Julian P Vivian
Major histocompatibility complex class I (MHC-I) molecules play a crucial role in immunity by capturing peptides for presentation to T cells and natural killer (NK) cells. The peptide termini are tethered within the MHC-I antigen-binding groove, but it is unknown whether other presentation modes occur. Here we show that 20% of the HLA-B*57:01 peptide repertoire comprises N-terminally extended sets characterized by a common motif at position 1 (P1) to P2. Structures of HLA-B*57:01 presenting N-terminally extended peptides, including the immunodominant HIV-1 Gag epitope TW10 (TSTLQEQIGW), showed that the N terminus protrudes from the peptide-binding groove...
April 2017: Nature Structural & Molecular Biology
Eilon Barnea, Dganit Melamed Kadosh, Yael Haimovich, Nimman Satumtira, Martha L Dorris, Mylinh T Nguyen, Robert E Hammer, Tri M Tran, Robert A Colbert, Joel D Taurog, Arie Admon
HLA-B27 is a class I major histocompatibility (MHC-I) allele that confers susceptibility to the rheumatic disease ankylosing spondylitis (AS) by an unknown mechanism. ERAP1 is an aminopeptidase that trims peptides in the endoplasmic reticulum for binding to MHC-I molecules. ERAP1 shows genetic epistasis with HLA-B27 in conferring susceptibility to AS. Male HLA-B27 transgenic rats develop arthritis and serve as an animal model of AS, whereas female B27 transgenic rats remain healthy. We used large scale quantitative mass spectrometry to identify over 15,000 unique HLA-B27 peptide ligands, isolated after immunoaffinity purification of the B27 molecules from the spleens of HLA-B27 transgenic rats...
April 2017: Molecular & Cellular Proteomics: MCP
Linus Backert, Daniel Johannes Kowalewski, Simon Walz, Heiko Schuster, Claudia Berlin, Marian Christoph Neidert, Mirle Schemionek, Tim H Brümmendorf, Vladan Vucinic, Dietger Niederwieser, Lothar Kanz, Helmut Rainer Salih, Oliver Kohlbacher, Katja Weisel, Hans-Georg Rammensee, Stefan StevanoviÄ, Juliane Sarah Walz
Hematological malignancies (HM) are highly amenable targets for immunotherapeutic intervention and may be effectively treated by antigen-specific T-cell based treatment. Recent studies demonstrate that physiologically occurring anti-cancer T-cell responses in certain HM entities target broadly presented non-mutated epitopes. HLA ligands are thus implied as prime targets for broadly applicable and antigen-specific off-the-shelf compounds. With the aim of assessing the presence of common targets shared among different HM which may enable addressing a larger patient collective we conducted a meta-analysis of 83 mass spectrometry-based HLA peptidome datasets (comprising 40,361 unique peptide identifications) across four major HM (19 AML, 16 CML, 35 CLL, and 13 MM/MCL samples) and investigated similarities and differences within the HLA presented antigenic landscape...
January 31, 2017: Oncotarget
Tim Fugmann, Adriana Sofron, Danilo Ritz, Franziska Bootz, Dario Neri
We recently described a mass spectrometry-based methodology that enables the confident identification of hundreds of peptides bound to murine MHC class II (MHCII) molecules. In this article, we describe its application to the characterization of MHCII-bound peptides isolated from lymph nodes (LNs) of C57BL/6 mice. More than 1000 peptides could be identified in individual analyses, allowing a direct comparison of the MHCII peptidome in different types of normal LNs or in animals with colitis. The peptide length distribution and consensus sequences in axillary, brachial, inguinal, and mesenteric LNs were virtually identical, and a substantial portion of identified peptides corresponded to proteins found in all LNs...
December 23, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Michal Bassani-Sternberg, Eva Bräunlein, Richard Klar, Thomas Engleitner, Pavel Sinitcyn, Stefan Audehm, Melanie Straub, Julia Weber, Julia Slotta-Huspenina, Katja Specht, Marc E Martignoni, Angelika Werner, Rüdiger Hein, Dirk H Busch, Christian Peschel, Roland Rad, Jürgen Cox, Matthias Mann, Angela M Krackhardt
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...
November 21, 2016: Nature Communications
Danilo Ritz, Andreas Gloger, Dario Neri, Tim Fugmann
Soluble human leukocyte antigen class I (sHLA)-peptide complexes have been suggested to play a role in the modulation of immune responses and in immune evasion of cancer cells. The set of peptides eluted from sHLA molecules could serve as biomarker for the monitoring of patients with cancer or other conditions. Here, we describe an improved sHLA peptidomics methodology resulting in the identification of 1816 to 2761 unique peptide sequences from triplicate analyses of serum or plasma taken from three healthy donors...
January 2017: Proteomics
Juliane Liepe, Fabio Marino, John Sidney, Anita Jeko, Daniel E Bunting, Alessandro Sette, Peter M Kloetzel, Michael P H Stumpf, Albert J R Heck, Michele Mishto
The proteasome generates the epitopes presented on human leukocyte antigen (HLA) class I molecules that elicit CD8(+) T cell responses. Reports of proteasome-generated spliced epitopes exist, but they have been regarded as rare events. Here, however, we show that the proteasome-generated spliced peptide pool accounts for one-third of the entire HLA class I immunopeptidome in terms of diversity and one-fourth in terms of abundance. This pool also represents a unique set of antigens, possessing particular and distinguishing features...
October 21, 2016: Science
Tina Heyder, Maxie Kohler, Nataliya K Tarasova, Sabrina Haag, Dorothea Rutishauser, Natalia V Rivera, Charlotta Sandin, Sohel Mia, Vivianne Malmström, Åsa M Wheelock, Jan Wahlström, Rikard Holmdahl, Anders Eklund, Roman A Zubarev, Johan Grunewald, A Jimmy Ytterberg
Immune-mediated diseases strongly associating with human leukocyte antigen (HLA) alleles are likely linked to specific antigens. These antigens are presented to T cells in the form of peptides bound to HLA molecules on antigen presenting cells, e.g. dendritic cells, macrophages or B cells. The identification of HLA-DR-bound peptides presents a valuable tool to investigate the human immunopeptidome. The lung is likely a key player in the activation of potentially auto-aggressive T cells prior to entering target tissues and inducing autoimmune disease...
September 2016: Molecular & Cellular Proteomics: MCP
Markus W Löffler, P Anoop Chandran, Karoline Laske, Christopher Schroeder, Irina Bonzheim, Mathias Walzer, Franz J Hilke, Nico Trautwein, Daniel J Kowalewski, Heiko Schuster, Marc Günder, Viviana A Carcamo Yañez, Christopher Mohr, Marc Sturm, Huu-Phuc Nguyen, Olaf Riess, Peter Bauer, Sven Nahnsen, Silvio Nadalin, Derek Zieker, Jörg Glatzle, Karolin Thiel, Nicole Schneiderhan-Marra, Stephan Clasen, Hans Bösmüller, Falko Fend, Oliver Kohlbacher, Cécile Gouttefangeas, Stefan Stevanović, Alfred Königsrainer, Hans-Georg Rammensee
BACKGROUND & AIMS: We report a novel experimental immunotherapeutic approach in a patient with metastatic intrahepatic cholangiocarcinoma. In the 5year course of the disease, the initial tumor mass, two local recurrences and a lung metastasis were surgically removed. Lacking alternative treatment options, aiming at the induction of anti-tumor T cells responses, we initiated a personalized multi-peptide vaccination, based on in-depth analysis of tumor antigens (immunopeptidome) and sequencing...
October 2016: Journal of Hepatology
Michal Bassani-Sternberg, George Coukos
The antigenic landscape of tumors is distinct from healthy cells and has been the rationale behind a variety of vaccination trials. Typically the target tumor-associated antigens have been of self origin and have rarely induced effective anti-tumor responses. Recent data show that activation of the immune system by immune checkpoint blocking therapies leads to tumor rejection and that recognition of mutated antigens, known as 'neo-antigens' plays a key role. Discovery of neo-antigens relies mainly on prediction-based interrogation of the 'mutanome' using genomic information as input, followed by T-cell screening...
August 2016: Current Opinion in Immunology
Anthony W Purcell, Nathan P Croft, David C Tscharke
We review approaches to quantitate antigen presentation using a variety of biological and biochemical readouts and highlight the emerging role of mass spectrometry (MS) in defining and quantifying MHC-bound peptides presented at the cell surface. The combination of high mass accuracy in the determination of the molecular weight of the intact peptide of interest and its signature pattern of fragmentation during tandem MS provide an unambiguous and definitive identification. This is in contrast to the potential receptor cross-reactivity towards closely related peptides and variable dose responsiveness seen in biological readouts...
June 2016: Current Opinion in Immunology
Lawrence J Stern, Laura Santambrogio
Recent advances in mass spectrometry technology have facilitated detailed examination of MHC-II immunopeptidomes, for example the repertoires of peptides bound to MHC-II molecules expressed in antigen presenting cells. These studies have deepened our view of MHC-II presentation. Other studies have broadened our view of pathways leading up to peptide loading. Here we review these recent studies in the context of earlier work on conventional and non-conventional MHC-II processing. The message that emerges is that sources of antigen beyond conventional endosomal processing of endocytosed proteins are important for generation of cellular immune responses to pathogens and maintenance of central and peripheral tolerance...
June 2016: Current Opinion in Immunology
Pouya Faridi, Ruedi Aebersold, Etienne Caron
We present the first standardized HLA peptidomics dataset generated by the immunopeptidomics community. The dataset is composed of native HLA class I peptides as well as synthetic HLA class II peptides that were acquired in data-dependent acquisition mode using multiple types of mass spectrometers. All laboratories used the spiked-in landmark iRT peptides for retention time normalization and data analysis. The mass spectrometric data were deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD001872...
June 2016: Data in Brief
Etienne Caron, Daniel J Kowalewski, Ching Chiek Koh, Theo Sturm, Heiko Schuster, Ruedi Aebersold
The myriad of peptides presented at the cell surface by class I and class II major histocompatibility complex (MHC) molecules are referred to as the immunopeptidome and are of great importance for basic and translational science. For basic science, the immunopeptidome is a critical component for understanding the immune system; for translational science, exact knowledge of the immunopeptidome can directly fuel and guide the development of next-generation vaccines and immunotherapies against autoimmunity, infectious diseases, and cancers...
December 2015: Molecular & Cellular Proteomics: MCP
Robin B Hartholt, Ivan Peyron, Jan Voorberg
Major histocompatibility complex class II (MHCII)-restricted peptide presentation is crucial for the selection and subsequent proliferation of antigen specific CD4+ T cells. While selection of antigen-specific CD4+ T cells is beneficial in the context of vaccination, emergence of antigen CD4+ T cells following administration of therapeutic proteins like factor VIII (FVIII) is not desirable. The mechanism of uptake, processing and presentation of FVIII by antigen-presenting cells (APCs) has been the subject of intense study over the past 10 years...
March 2016: Cellular Immunology
Nicola Ternette, Hongbing Yang, Thomas Partridge, Anuska Llano, Samandhy Cedeño, Roman Fischer, Philip D Charles, Nadine L Dudek, Beatriz Mothe, Manuel Crespo, William M Fischer, Bette T M Korber, Morten Nielsen, Persephone Borrow, Anthony W Purcell, Christian Brander, Lucy Dorrell, Benedikt M Kessler, Tomáš Hanke
Recognition and eradication of infected cells by cytotoxic T lymphocytes is a key defense mechanism against intracellular pathogens. High-throughput definition of HLA class I-associated immunopeptidomes by mass spectrometry is an increasingly important analytical tool to advance our understanding of the induction of T-cell responses against pathogens such as HIV-1. We utilized a liquid chromatography tandem mass spectrometry workflow including de novo-assisted database searching to define the HLA class I-associated immunopeptidome of HIV-1-infected human cells...
January 2016: European Journal of Immunology
Ingrid M M Schellens, Ilka Hoof, Hugo D Meiring, Sanne N M Spijkers, Martien C M Poelen, Jacqueline A M van Gaans-van den Brink, Kees van der Poel, Ana I Costa, Cecile A C M van Els, Debbie van Baarle, Can Kesmir
The cytotoxic T cell (CTL) response is determined by the peptide repertoire presented by the HLA class I molecules of an individual. We performed an in-depth analysis of the peptide repertoire presented by a broad panel of common HLA class I molecules on four B lymphoblastoid cell-lines (BLCL). Peptide elution and mass spectrometry analysis were utilised to investigate the number and abundance of self-peptides. Altogether, 7897 unique self-peptides, derived of 4344 proteins, were eluted. After viral infection, the number of unique self-peptides eluted significantly decreased compared to uninfected cells, paralleled by a decrease in the number of source proteins...
2015: PloS One
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