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101. eta-Secretase processing of APP inhibits neuronal activity in the hippocampus

Author

Willem, Michael, Tahirovic, Sabina, Busche, Marc Aurel, Ovsepian, Saak V., Chafai, Magda, Kootar, Scherazad, Hornburg, Daniel, Evans, Lewis D. B., Moore, Steven, Daria, Anna, Hampel, Heike, Mueller, Veronika, Giudici, Camilla, Nuscher, Brigitte, Wenninger-Weinzierl, Andrea, Kremmer, Elisabeth, Heneka, Michael T., Thal, Dietmar R., Giedraitis, Vilmantas, Lannfelt, Lars, Mueller, Ulrike, Livesey, Frederick J., Meissner, Felix, Herms, Jochen, Konnerth, Arthur, Marie, Helene, Haass, Christian, Willem, Michael, Tahirovic, Sabina, Busche, Marc Aurel, Ovsepian, Saak V., Chafai, Magda, Kootar, Scherazad, Hornburg, Daniel, Evans, Lewis D. B., Moore, Steven, Daria, Anna, Hampel, Heike, Mueller, Veronika, Giudici, Camilla, Nuscher, Brigitte, Wenninger-Weinzierl, Andrea, Kremmer, Elisabeth, Heneka, Michael T., Thal, Dietmar R., Giedraitis, Vilmantas, Lannfelt, Lars, Mueller, Ulrike, Livesey, Frederick J., Meissner, Felix, Herms, Jochen, Konnerth, Arthur, Marie, Helene, and Haass, Christian

Abstract

Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-beta peptide(1). Two principal physiological pathways either prevent or promote amyloid-beta generation from its precursor, beta-amyloid precursor protein (APP), in a competitive manne(r)1. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo(2). Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-eta, in addition to the long-known CTF-alpha and CTF-beta fragments generated by the alpha- and beta-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (beta-site APP cleaving enzyme 1), respectively. CTF-eta generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as g-secretase activity. g-Secretase cleavage occurs primarily at amino acids 504-505 of APP(695), releasing a truncated ectodomain. After shedding of this ectodomain, CTF-eta is further processed by ADAM10 and BACE1 to release long and short A eta peptides (termed A eta-alpha and A eta-beta). CTFs produced by g-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-eta and A eta-alpha. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic A eta-alpha was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by A eta-alpha. These findings not only demonstrate a major functionally relevant APP pr

Published
2015
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102. Quantitative Proteomics Identifies Serum Response Factor Binding Protein 1 as a Host Factor for Hepatitis C Virus Entry

Author

Gerold, Gisa, Meissner, Felix, Bruening, Janina, Welsch, Kathrin, Perin, Paula M, Baumert, Thomas F, Vondran, Florian W, Kaderali, Lars, Marcotrigiano, Joseph, Khan, Abdul G, Mann, Matthias, Rice, Charles M, Pietschmann, Thomas, Gerold, Gisa, Meissner, Felix, Bruening, Janina, Welsch, Kathrin, Perin, Paula M, Baumert, Thomas F, Vondran, Florian W, Kaderali, Lars, Marcotrigiano, Joseph, Khan, Abdul G, Mann, Matthias, Rice, Charles M, and Pietschmann, Thomas

Abstract

Hepatitis C virus (HCV) enters human hepatocytes through a multistep mechanism involving, among other host proteins, the virus receptor CD81. How CD81 governs HCV entry is poorly characterized, and CD81 protein interactions after virus binding remain elusive. We have developed a quantitative proteomics protocol to identify HCV-triggered CD81 interactions and found 26 dynamic binding partners. At least six of these proteins promote HCV infection, as indicated by RNAi. We further characterized serum response factor binding protein 1 (SRFBP1), which is recruited to CD81 during HCV uptake and supports HCV infection in hepatoma cells and primary human hepatocytes. SRFBP1 facilitates host cell penetration by all seven HCV genotypes, but not of vesicular stomatitis virus and human coronavirus. Thus, SRFBP1 is an HCV-specific, pan-genotypic host entry factor. These results demonstrate the use of quantitative proteomics to elucidate pathogen entry and underscore the importance of host protein-protein interactions during HCV invasion.

Published
2015
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103. Secretome Analysis of Lipid-Induced Insulin Resistance in Skeletal Muscle Cells by a Combined Experimental and Bioinformatics Workflow

Author

Deshmukh, Atul S, Cox, Juergen, Jensen, Lars Juhl, Meissner, Felix, Mann, Matthias, Deshmukh, Atul S, Cox, Juergen, Jensen, Lars Juhl, Meissner, Felix, and Mann, Matthias

Abstract

Skeletal muscle has emerged as an important secretory organ that produces so-called myokines, regulating energy metabolism via autocrine, paracrine, and endocrine actions; however, the nature and extent of the muscle secretome has not been fully elucidated. Mass spectrometry (MS)-based proteomics, in principle, allows an unbiased and comprehensive analysis of cellular secretomes; however, the distinction of bona fide secreted proteins from proteins released upon lysis of a small fraction of dying cells remains challenging. Here we applied highly sensitive MS and streamlined bioinformatics to analyze the secretome of lipid-induced insulin-resistant skeletal muscle cells. Our workflow identified 1073 putative secreted proteins including 32 growth factors, 25 cytokines, and 29 metalloproteinases. In addition to previously reported proteins, we report hundreds of novel ones. Intriguingly, ∼40% of the secreted proteins were regulated under insulin-resistant conditions, including a protein family with signal peptide and EGF-like domain structure that had not yet been associated with insulin resistance. Finally, we report that secretion of IGF and IGF-binding proteins was down-regulated under insulin-resistant conditions. Our study demonstrates an efficient combined experimental and bioinformatics workflow to identify putative secreted proteins from insulin-resistant skeletal muscle cells, which could easily be adapted to other cellular models.

Published
2015

104. Evidence of Extrapancreatic Glucagon Secretion in Man

Author

Lund, Asger, primary, Bagger, Jonatan I., additional, Wewer Albrechtsen, Nicolai J., additional, Christensen, Mikkel, additional, Grøndahl, Magnus, additional, Hartmann, Bolette, additional, Mathiesen, Elisabeth R., additional, Hansen, Carsten P., additional, Storkholm, Jan H., additional, van Hall, Gerrit, additional, Rehfeld, Jens F., additional, Hornburg, Daniel, additional, Meissner, Felix, additional, Mann, Matthias, additional, Larsen, Steen, additional, Holst, Jens J., additional, Vilsbøll, Tina, additional, and Knop, Filip K., additional

Published
2015
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106. Interleukin-1 Antagonist Anakinra in Amyotrophic Lateral Sclerosis—A Pilot Study

Author

Maier, André, primary, Deigendesch, Nikolaus, additional, Müller, Kathrin, additional, Weishaupt, Jochen H., additional, Krannich, Alexander, additional, Röhle, Robert, additional, Meissner, Felix, additional, Molawi, Kaaweh, additional, Münch, Christoph, additional, Holm, Teresa, additional, Meyer, Robert, additional, Meyer, Thomas, additional, and Zychlinsky, Arturo, additional

Published
2015
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107. Functional classification of memory CD8+ T cells by CX3CR1 expression

Author

Böttcher, Jan P., primary, Beyer, Marc, additional, Meissner, Felix, additional, Abdullah, Zeinab, additional, Sander, Jil, additional, Höchst, Bastian, additional, Eickhoff, Sarah, additional, Rieckmann, Jan C., additional, Russo, Caroline, additional, Bauer, Tanja, additional, Flecken, Tobias, additional, Giesen, Dominik, additional, Engel, Daniel, additional, Jung, Steffen, additional, Busch, Dirk H., additional, Protzer, Ulrike, additional, Thimme, Robert, additional, Mann, Matthias, additional, Kurts, Christian, additional, Schultze, Joachim L., additional, Kastenmüller, Wolfgang, additional, and Knolle, Percy A., additional

Published
2015
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108. TLR3-Mediated CD8+ Dendritic Cell Activation Is Coupled with Establishment of a Cell-Intrinsic Antiviral State

Author

Széles, Lajos, primary, Meissner, Felix, additional, Dunand-Sauthier, Isabelle, additional, Thelemann, Christoph, additional, Hersch, Micha, additional, Singovski, Simon, additional, Haller, Sergio, additional, Gobet, Florian, additional, Fuertes Marraco, Silvia A., additional, Mann, Matthias, additional, Garcin, Dominique, additional, Acha-Orbea, Hans, additional, and Reith, Walter, additional

Published
2015
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109. Quantitative Proteomics Identifies Serum Response Factor Binding Protein 1 as a Host Factor for Hepatitis C Virus Entry

Author

Gerold, Gisa, primary, Meissner, Felix, additional, Bruening, Janina, additional, Welsch, Kathrin, additional, Perin, Paula M., additional, Baumert, Thomas F., additional, Vondran, Florian W., additional, Kaderali, Lars, additional, Marcotrigiano, Joseph, additional, Khan, Abdul G., additional, Mann, Matthias, additional, Rice, Charles M., additional, and Pietschmann, Thomas, additional

Published
2015
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110. Complex regulation of nucleic-acid sensing TLRs by UNC93B1

Author

Pelka, Karin, Phulphagar, Kshiti, Zimmermann, Jana, Schmid-Burgk, Jonathan, Schmidt, Tobias, Stahl, Rainer, Casanova, Jean-Laurent, Meissner, Felix, Hornung, Veit, Hoening, Stefan, Latz, Eicke, Pelka, Karin, Phulphagar, Kshiti, Zimmermann, Jana, Schmid-Burgk, Jonathan, Schmidt, Tobias, Stahl, Rainer, Casanova, Jean-Laurent, Meissner, Felix, Hornung, Veit, Hoening, Stefan, and Latz, Eicke

Published
2014

112. 177

Author

Stutz, Andrea, primary, Horvath, Gabor L., additional, Stahl, Rainer, additional, Franklin, Bernardo S., additional, Kolbe, Carl-Christian L., additional, Geyer, Matthias, additional, Meissner, Felix, additional, and Latz, Eicke, additional

Published
2014
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113. 146

Author

Pelka, Karin, primary, Phulphagar, Kshiti, additional, Zimmermann, Jana, additional, Schmid-Burgk, Jonathan, additional, Schmidt, Tobias, additional, Stahl, Rainer, additional, Casanova, Jean-Laurent, additional, Meissner, Felix, additional, Hornung, Veit, additional, Hoening, Stefan, additional, and Latz, Eicke, additional

Published
2014
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118. Novel Murine Dendritic Cell Lines: A Powerful Auxiliary Tool for Dendritic Cell Research

Author

Fuertes Marraco, Silvia A., primary, Grosjean, Frédéric, additional, Duval, Anaïs, additional, Rosa, Muriel, additional, Lavanchy, Christine, additional, Ashok, Devika, additional, Haller, Sergio, additional, Otten, Luc A., additional, Steiner, Quynh-Giao, additional, Descombes, Patrick, additional, Luber, Christian A., additional, Meissner, Felix, additional, Mann, Matthias, additional, Szeles, Lajos, additional, Reith, Walter, additional, and Acha-Orbea, Hans, additional

Published
2012
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120. TLR3-Mediated CD8+ Dendritic Cell Activation Is Coupled with Establishment of a Cell-Intrinsic Antiviral State.

Author

Széles, Lajos, Meissner, Felix, Dunand-Sauthier, Isabelle, Thelemann, Christoph, Hersch, Micha, Singovski, Simon, Haller, Sergio, Gobet, Florian, Fuertes Marraco, Silvia A., Mann, Matthias, Garcin, Dominique, Acha-Orbea, Hans, and Reith, Walter

Subjects
*TOLL-like receptors, *DENDRITIC cells, *CD8 antigen, *IMMUNOREGULATION, *MASS spectrometry, *AUTOCRINE mechanisms
Abstract

Because of their unique capacity to cross-present Ags to CD8+ T cells, mouse lymphoid tissue-resident CD8+ dendritic cells (DCs) and their migratory counterparts are critical for priming antiviral T cell responses. High expression of the dsRNA sensor TLR3 is a distinctive feature of these cross-presenting DC subsets. TLR3 engagement in CD8+ DCs promotes cross-presentation and the acquisition of effector functions required for driving antiviral T cell responses. In this study, we performed a comprehensive analysis of the TLR3-induced antiviral program and cell-autonomous immunity in CD8+ DC lines and primary CD8+ DCs. We found that TLR3-ligand polyinosinic-polycytidylic acid and human rhinovirus infection induced a potent antiviral protection against Sendai and vesicular stomatitis virus in a TLR3 and type I IFN receptor-dependent manner. Polyinosinic-polycytidylic acid-induced antiviral genes were identified by mass spectrometry-based proteomics and transcriptomics in the CD8+ DC line. Nanostring nCounter experiments confirmed that these antiviral genes were induced by TLR3 engagement in primary CD8+ DCs, and indicated that many are secondary TLR3-response genes requiring autocrine IFN-β stimulation. TLR3-activation thus establishes a type I IFN-dependent antiviral program in a DC subtype playing crucial roles in priming adaptive antiviral immune responses. This mechanism is likely to shield the priming of antiviral responses against inhibition or abrogation by the viral infection. It could be particularly relevant for viruses detected mainly by TLR3, which may not trigger type I IFN production by DCs that lack TLR3, such as plasmacytoid DCs or CD8- DCs. [ABSTRACT FROM AUTHOR]

Published
2015
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121. P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection

Author

Jenster, Lea-Marie, Lange, Karl-Elmar, Normann, Sabine, vom Hemdt, Anja, Wuerth, Jennifer D., Schiffelers, Lisa D.J., Tesfamariam, Yonas M., Gohr, Florian N., Klein, Laura, Kaltheuner, Ines H., Ebner, Stefan, Lapp, Dorothee J., Mayer, Jacob, Moecking, Jonas, Ploegh, Hidde L., Latz, Eicke, Meissner, Felix, Geyer, Matthias, Kümmerer, Beate M., and Schmidt, Florian I.

Abstract

Inflammasomes integrate cytosolic evidence of infection or damage to mount inflammatory responses. The inflammasome sensor NLRP1 is expressed in human keratinocytes and coordinates inflammation in the skin. We found that diverse stress signals induce human NLRP1 inflammasome assembly by activating MAP kinase p38: While the ribotoxic stress response to UV and microbial molecules exclusively activates p38 through MAP3K ZAKα, infection with arthropod-borne alphaviruses, including Semliki Forest and Chikungunya virus, activates p38 through ZAKα and potentially other MAP3K. We demonstrate that p38 directly phosphorylates NLRP1 and that serine 107 in the linker region is critical for activation. NLRP1 phosphorylation is followed by ubiquitination of NLRP1PYD, N-terminal degradation of NLRP1, and nucleation of inflammasomes by NLRP1UPA-CARD. In contrast, activation of NLRP1 by nanobody-mediated ubiquitination, viral proteases, or inhibition of DPP9 was independent of p38 activity. Taken together, we define p38 activation as a unifying signaling hub that controls NLRP1 inflammasome activation by integrating a variety of cellular stress signals relevant to the skin.

Published
2023
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122. Wait Before You Learn - How Organizational Structure Shapes Learning Paths.

Author

Meissner, Felix

Abstract

Hierarchical structures -- here understood as the intra- organizational arrangement of lines of authority, information flows and roles of organizational members -- have been traditionally assumed to inhibit organizational learning and impede an organization's adaptability. We revisit this assumption, which is based on the logic that hierarchies may hinder the accurate processing and delay the internal forwarding of performance feedback, thereby foregoing the opportunity to learn and quickly adapt behavior in a way that increases performance. We argue that this logic is incomplete. A delay in feedback forwarding may also influence the characteristics of the learning process, in particular the search paths and focus of exploratory activities. Employing a simulation model, we examine how organizations search and experiment with new solutions when performance feedback on past actions is delayed and ambiguous. Contrary to conventional wisdom, our analysis uncovers mechanisms of deeper exploration by which hierarchical structures may improve, rather than impede learning and performance improvements in the long run. Our model shows that hierarchies both influence the speed of interpreting and learning from performance feedback as well as the search paths taken to explore alternatives." [ABSTRACT FROM AUTHOR]

Published
2020
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123. Multiple Goals and Multiple Aspirations: New Questions, New Perspectives.

Author

Baumann, Oliver, Newark, Daniel, Sump, Franziska, Audia, Pino G., Bettis, Richard A., Blettner, Daniela, Syrigos, Evangelos, Wahle, Thorsten, Gollisch, Simon, Kostopoulos, Konstantinos Christos, Martignoni, Dirk, and Meissner, Felix

Abstract

It is common to view organizations as instruments to pursue collective goals. But beyond recognizing the presence of organizational goals, important questions relate to how these goals come about and drive organizational behavior. These questions are particularly relevant because organizations are typically characterized by the presence of multiple, and often conflicting, goals. Starting with the seminal work on the Behavioral Theory of the Firm, various lines of research have studied how organizations form goals, set aspirations as reference points for evaluating goal attainment, and change behavior and aspirations in response to performance feedback. Yet this work notwithstanding, many exciting questions remain for both theoretical and empirical research at various levels of analysis. For this symposium, we have assembled a set of (predominantly) younger scholars that are working on a variety of issues related to multiple goals and multiple aspirations, as well as two preeminent experts on the topic who will serve as discussants. The symposium pursues two broad objectives: One is to showcase and discuss four different projects that probe intriguing unresolved questions at different conceptual levels, relate to different discussions in the literature, and use different models and methodologies. The second objective is to stimulate a fruitful conversation about how future research can further improve our understanding of how organizations set and pursue multiple goals and aspirations. [ABSTRACT FROM AUTHOR]

Published
2020
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124. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author

Pfister, Dominik, Núñez, Nicolás Gonzalo, Pinyol, Roser, Govaere, Olivier, Pinter, Matthias, Szydlowska, Marta, Gupta, Revant, Qiu, Mengjie, Deczkowska, Aleksandra, Weiner, Assaf, Müller, Florian, Sinha, Ankit, Friebel, Ekaterina, Engleitner, Thomas, Lenggenhager, Daniela, Moncsek, Anja, Heide, Danijela, Stirm, Kristin, Kosla, Jan, Kotsiliti, Eleni, Leone, Valentina, Dudek, Michael, Yousuf, Suhail, Inverso, Donato, Singh, Indrabahadur, Teijeiro, Ana, Castet, Florian, Montironi, Carla, Haber, Philipp K, Tiniakos, Dina, Bedossa, Pierre, Cockell, Simon, Younes, Ramy, Vacca, Michele, Marra, Fabio, Schattenberg, Jörn M, Allison, Michael, Bugianesi, Elisabetta, Ratziu, Vlad, Pressiani, Tiziana, D'Alessio, Antonio, Personeni, Nicola, Rimassa, Lorenza, Daly, Ann K, Scheiner, Bernhard, Pomej, Katharina, Kirstein, Martha M, Vogel, Arndt, Peck-Radosavljevic, Markus, Hucke, Florian, Finkelmeier, Fabian, Waidmann, Oliver, Trojan, Jörg, Schulze, Kornelius, Wege, Henning, Koch, Sandra, Weinmann, Arndt, Bueter, Marco, Rössler, Fabian, Siebenhüner, Alexander, De Dosso, Sara, Mallm, Jan-Philipp, Umansky, Viktor, Jugold, Manfred, Luedde, Tom, Schietinger, Andrea, Schirmacher, Peter, Emu, Brinda, Augustin, Hellmut G, Billeter, Adrian, Müller-Stich, Beat, Kikuchi, Hiroto, Duda, Dan G, Kütting, Fabian, Waldschmidt, Dirk-Thomas, Ebert, Matthias Philip, Rahbari, Nuh, Mei, Henrik E, Schulz, Axel Ronald, Ringelhan, Marc, Malek, Nisar, Spahn, Stephan, Bitzer, Michael, Ruiz De Galarreta, Marina, Lujambio, Amaia, Dufour, Jean-Francois, Marron, Thomas U, Kaseb, Ahmed, Kudo, Masatoshi, Huang, Yi-Hsiang, Djouder, Nabil, Wolter, Katharina, Zender, Lars, Marche, Parice N, Decaens, Thomas, Pinato, David J, Rad, Roland, Mertens, Joachim C, Weber, Achim, Unger, Kristian, Meissner, Felix, Roth, Susanne, Jilkova, Zuzana Macek, Claassen, Manfred, Anstee, Quentin M, Amit, Ido, Knolle, Percy, Becher, Burkhard, Llovet, Josep M, and Heikenwalder, Mathias

Subjects
Male, Carcinoma, Hepatocellular, Carcinogenesis, Tumor Necrosis Factor-alpha, Liver Neoplasms, Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, digestive system diseases, B7-H1 Antigen, 3. Good health, Mice, Liver, Non-alcoholic Fatty Liver Disease, Disease Progression, Animals, Humans, Immunotherapy
Abstract

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

125. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity

Author

Geiger, Roger, Rieckmann, Jan C., Wolf, Tobias, Basso, Camilla, Feng, Yuehan, Fuhrer, Tobias, Kogadeeva, Maria, Picotti, Paola, Meissner, Felix, Mann, Matthias, Zamboni, Nicola, Sallusto, Federica, and Lanzavecchia, Antonio

Subjects
Metabolism, Proteome, Metabolome, L-arginine, T cell, Cancer immunotherapy, LiP-MS, Metabolite sensing, 3. Good health, T cell survival
Abstract

Metabolic activity is intimately linked to T cell fate and function. Using high-resolution mass spectrometry, we generated dynamic metabolome and proteome profiles of human primary naive T cells following activation. We discovered critical changes in the arginine metabolism that led to a drop in intracellular L-arginine concentration. Elevating L-arginine levels induced global metabolic changes including a shift from glycolysis to oxidative phosphorylation in activated T cells and promoted the generation of central memory-like cells endowed with higher survival capacity and, in a mouse model, anti-tumor activity. Proteome-wide probing of structural alterations, validated by the analysis of knockout T cell clones, identified three transcriptional regulators (BAZ1B, PSIP1, and TSN) that sensed L-arginine levels and promoted T cell survival. Thus, intracellular L-arginine concentrations directly impact the metabolic fitness and survival capacity of T cells that are crucial for anti-tumor responses., Cell, 167 (3), ISSN:0092-8674, ISSN:1097-4172

126. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author

Pfister, Dominik, Núñez, Nicolás Gonzalo, Pinyol, Roser, Govaere, Olivier, Pinter, Matthias, Szydlowska, Marta, Gupta, Revant, Qiu, Mengjie, Deczkowska, Aleksandra, Weiner, Assaf, Müller, Florian, Sinha, Ankit, Friebel, Ekaterina, Engleitner, Thomas, Lenggenhager, Daniela, Moncsek, Anja, Heide, Danijela, Stirm, Kristin, Kosla, Jan, Kotsiliti, Eleni, Leone, Valentina, Dudek, Michael, Yousuf, Suhail, Inverso, Donato, Singh, Indrabahadur, Teijeiro, Ana, Castet, Florian, Montironi, Carla, Haber, Philipp K, Tiniakos, Dina, Bedossa, Pierre, Cockell, Simon, Younes, Ramy, Vacca, Michele, Marra, Fabio, Schattenberg, Jörn M, Allison, Michael, Bugianesi, Elisabetta, Ratziu, Vlad, Pressiani, Tiziana, D'Alessio, Antonio, Personeni, Nicola, Rimassa, Lorenza, Daly, Ann K, Scheiner, Bernhard, Pomej, Katharina, Kirstein, Martha M, Vogel, Arndt, Peck-Radosavljevic, Markus, Hucke, Florian, Finkelmeier, Fabian, Waidmann, Oliver, Trojan, Jörg, Schulze, Kornelius, Wege, Henning, Koch, Sandra, Weinmann, Arndt, Bueter, Marco, Rössler, Fabian, Siebenhüner, Alexander, De Dosso, Sara, Mallm, Jan-Philipp, Umansky, Viktor, Jugold, Manfred, Luedde, Tom, Schietinger, Andrea, Schirmacher, Peter, Emu, Brinda, Augustin, Hellmut G, Billeter, Adrian, Müller-Stich, Beat, Kikuchi, Hiroto, Duda, Dan G, Kütting, Fabian, Waldschmidt, Dirk-Thomas, Ebert, Matthias Philip, Rahbari, Nuh, Mei, Henrik E, Schulz, Axel Ronald, Ringelhan, Marc, Malek, Nisar, Spahn, Stephan, Bitzer, Michael, Ruiz de Galarreta, Marina, Lujambio, Amaia, Dufour, Jean-François, Marron, Thomas U, Kaseb, Ahmed, Kudo, Masatoshi, Huang, Yi-Hsiang, Djouder, Nabil, Wolter, Katharina, Zender, Lars, Marche, Parice N, Decaens, Thomas, Pinato, David J, Rad, Roland, Mertens, Joachim C, Weber, Achim, Unger, Kristian, Meissner, Felix, Roth, Susanne, Jilkova, Zuzana Macek, Claassen, Manfred, Anstee, Quentin M, Amit, Ido, Knolle, Percy, Becher, Burkhard, Llovet, Josep M, and Heikenwalder, Mathias

Subjects
610 Medicine & health, digestive system diseases, 3. Good health
Abstract

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

127. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author

Pfister, Dominik, Núñez, Nicolás Gonzalo, Pinyol, Roser, Govaere, Olivier, Pinter, Matthias, Szydlowska, Marta, Gupta, Revant, Qiu, Mengjie, Deczkowska, Aleksandra, Weiner, Assaf, Müller, Florian, Sinha, Ankit, Friebel, Ekaterina, Engleitner, Thomas, Lenggenhager, Daniela, Moncsek, Anja, Heide, Danijela, Stirm, Kristin, Kosla, Jan, Kotsiliti, Eleni, Leone, Valentina, Dudek, Michael, Yousuf, Suhail, Inverso, Donato, Singh, Indrabahadur, Teijeiro, Ana, Castet, Florian, Montironi, Carla, Haber, Philipp K., Tiniakos, Dina, Bedossa, Pierre, Cockell, Simon, Younes, Ramy, Vacca, Michele, Marra, Fabio, Schattenberg, Jörn M., Allison, Michael, Bugianesi, Elisabetta, Ratziu, Vlad, Pressiani, Tiziana, D’Alessio, Antonio, Personeni, Nicola, Rimassa, Lorenza, Daly, Ann K., Scheiner, Bernhard, Pomej, Katharina, Kirstein, Martha M., Vogel, Arndt, Peck-Radosavljevic, Markus, Hucke, Florian, Finkelmeier, Fabian, Waidmann, Oliver, Trojan, Jörg, Schulze, Kornelius, Wege, Henning, Koch, Sandra, Weinmann, Arndt, Bueter, Marco, Rössler, Fabian, Siebenhüner, Alexander, De Dosso, Sara, Mallm, Jan-Philipp, Umansky, Viktor, Jugold, Manfred, Luedde, Tom, Schietinger, Andrea, Schirmacher, Peter, Emu, Brinda, Augustin, Hellmut G., Billeter, Adrian, Müller-Stich, Beat, Kikuchi, Hiroto, Duda, Dan G., Kütting, Fabian, Waldschmidt, Dirk-Thomas, Ebert, Matthias Philip, Rahbari, Nuh, Mei, Henrik E., Schulz, Axel Ronald, Ringelhan, Marc, Malek, Nisar, Spahn, Stephan, Bitzer, Michael, Ruiz De Galarreta, Marina, Lujambio, Amaia, Dufour, Jean-Francois, Marron, Thomas U., Kaseb, Ahmed, Kudo, Masatoshi, Huang, Yi-Hsiang, Djouder, Nabil, Wolter, Katharina, Zender, Lars, Marche, Parice N., Decaens, Thomas, Pinato, David J., Rad, Roland, Mertens, Joachim C., Weber, Achim, Unger, Kristian, Meissner, Felix, Roth, Susanne, Jilkova, Zuzana Macek, Claassen, Manfred, Anstee, Quentin M., Amit, Ido, Knolle, Percy, Becher, Burkhard, Llovet, Josep M., and Heikenwalder, Mathias

Subjects
631/67, article, 631/250/251, digestive system diseases, 3. Good health, 13/31, 13/2, 14/32, 13/1, 14/34, 13/21, 13/51, 14/63, 59/57, 64/60, 14/19, 14/35
Abstract

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6, 7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

128. Functional classification of memory CD8+ T cells by CX3CR1 expression.

Author

Böttcher, Jan P., Beyer, Marc, Meissner, Felix, Abdullah, Zeinab, Sander, Jil, Höchst, Bastian, Eickhoff, Sarah, Rieckmann, Jan C., Russo, Caroline, Bauer, Tanja, Flecken, Tobias, Giesen, Dominik, Engel, Daniel, Jung, Steffen, Busch, Dirk H., Protzer, Ulrike, Thimme, Robert, Mann, Matthias, Kurts, Christian, and Schultze, Joachim L.

Published
2015
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129. Secretomics reveals gelatinase substrates at the bloodbrain barrier that are implicated in astroglial barrier function.

Author

Burmeister, Miriam, Fraunenstein, Annika, Kahms, Martin, Arends, Laura, Gerwien, Hanna, Deshpande, Tushar, Kuhlmann, Tanja, Gross, Catharina C., Naik, Venu N., Wiendl, Heinz, Klingauf, Juergen, Meissner, Felix, and Sorokin, Lydia

Subjects
*MEMBRANE proteins, *CELL adhesion molecules, *GLUTAMATE transporters, *PROTEOMICS, *CELL adhesion, *CYTOLOGY, *CADHERINS, *GELATIN
Abstract

The article offers information on the identification of gelatinase substrates at the blood-brain barrier that play a role in astroglial barrier function. Using a sensitive label-free mass spectrometry-based secretome approach, the study identifies potential substrates for MMP-9 and MMP-2 at the cell surface of primary astrocytes, including known substrates and previously unknown MMP-dependent events involved in cell-cell and cell-matrix interactions.

Published
2023
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130. Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA.

Author

Woemer, Andreas C., Frottin, Fréd#233;ric, Hornburg, Daniel, Meissner, Felix, Patra, Maria, Tatzelt, Jörg, Mann, Matthias, Winklhofer, Konstanze F., Haiti, F. Ulrich, Hipp, Mark S., and Li R. Feng

Subjects
*CYTOPLASM, *NUCLEOCYTOPLASMIC interactions, *PROTEIN transport, *RNA, *AMYLOID, *NEURODEGENERATION, *NUCLEOLUS
Abstract

Amyloid-like protein aggregation is associated with neurodegeneration and other pathologies. The nature of the toxic aggregate species and their mechanism of action remain elusive. Here, we analyzed the compartment specificity of aggregate toxicity using artificial p-sheet proteins, as well as fragments of mutant huntingtin and TAR DNA binding protein-43 (TDP-43). Aggregation in the cytoplasm interfered with nucleocytoplasmic protein and RNA transport. In contrast, the same proteins did not inhibit transport when forming inclusions in the nucleus at or around the nucleolus. Protein aggregation in the cytoplasm, but not the nucleus, caused the sequestration and mislocalization of proteins containing disordered and low-complexity sequences, including multiple factors of the nuclear import and export machinery. Thus, impairment of nucleocytoplasmic transport may contribute to the cellular pathology of various aggregate deposition diseases. [ABSTRACT FROM AUTHOR]

Published
2016
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131. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author

Stephan Spahn, Florian Müller, Revant Gupta, Dominik Pfister, Kornelius Schulze, Pierre Bedossa, Eleni Kotsiliti, Lars Zender, Mathias Heikenwalder, Nicolás Gonzalo Núñez, Peter Schirmacher, Axel Schulz, Jan Kosla, Adrian T. Billeter, Thomas Engleitner, Aleksandra Deczkowska, Danijela Heide, Donato Inverso, Susanne Roth, Olivier Govaere, Carla Montironi, Martha M. Kirstein, Dan G. Duda, Antonio D'Alessio, Jörn M. Schattenberg, Ekaterina Friebel, Tiziana Pressiani, F. Hucke, Jörg Trojan, Michael Bitzer, Suhail Yousuf, Bernhard Scheiner, Marina Ruiz de Galarreta, Markus Peck-Radosavljevic, Michael Allison, Nuh N. Rahbari, Simon Cockell, Brinda Emu, Ahmed Kaseb, David J. Pinato, Matthias P. Ebert, Joachim C. Mertens, Jean-François Dufour, Fabian Rössler, Achim Weber, Katharina Wolter, Thomas Decaens, Amaia Lujambio, Anja Moncsek, Daniela Lenggenhager, Katharina Pomej, Nisar P. Malek, Fabian Finkelmeier, Elisabetta Bugianesi, Valentina Leone, Ann K. Daly, Michael Dudek, Manfred Claassen, Zuzana Macek Jilkova, Henning Wege, Florian Castet, Marta Szydlowska, Beat P. Müller-Stich, Ramy Younes, Nicola Personeni, Philipp K. Haber, Marco Bueter, Manfred Jugold, Andrea Schietinger, Hiroto Kikuchi, Ido Amit, Sandra Koch, Dina Tiniakos, Ana Teijeiro, Jan-Philipp Mallm, Josep M. Llovet, Indrabahadur Singh, Percy A. Knolle, Sara De Dosso, Roland Rad, Arndt Vogel, Henrik E. Mei, Burkhard Becher, Nabil Djouder, Tom Luedde, Felix Meissner, Oliver Waidmann, Parice N. Marche, Viktor Umansky, Hellmut G. Augustin, Thomas U. Marron, Matthias Pinter, Mengjie Qiu, Arndt Weinmann, Ankit Sinha, Kristian Unger, Assaf Weiner, Vlad Ratziu, Quentin M. Anstee, Kristin Stirm, Yi Hsiang Huang, Alexander Siebenhüner, Fabian Kütting, Lorenza Rimassa, Dirk Waldschmidt, Masatoshi Kudo, Marc Ringelhan, Michele Vacca, Roser Pinyol, Fabio Marra, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Novo Nordisk A/S [Maløv, Denmark], Universität Zürich [Zürich] = University of Zurich (UZH), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Newcastle University [Newcastle], Medizinische Universität Wien = Medical University of Vienna, University of Tübingen, UniversitätsKlinikum Heidelberg, Weizmann Institute of Science [Rehovot, Israël], Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft, Technical University of Munich (TUM), University hospital of Zurich [Zurich], Helmholtz-Zentrum München (HZM), Heidelberg University, Spanish National Cancer Research Center (CNIO), Icahn School of Medicine at Mount Sinai [New York] (MSSM), National and Kapodistrian University of Athens (NKUA), University of Turin, Addenbrooke's Hospital, Cambridge University NHS Trust, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University Medical Center [Mainz], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Hannover Medical School [Hannover] (MHH), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Klinikum Klagenfurt am Wörthersee, Universitätsklinikum Frankfurt, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Oncology Institute of Southern Switzerland (IOSI), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Heidelberg University Hospital [Heidelberg], Medical Faculty [Mannheim], Massachusetts General Hospital [Boston], University of Cologne, Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, German Center for Infection Research, Partnersite Munich (DZIF), University Medical Center [Tubingen, Germany], Inselspital Bern, University of Bern, The University of Texas M.D. Anderson Cancer Center [Houston], Kindai University, National Yang Ming University (NYMU), Taipei Veterans General Hospital [Taiwan], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Eberhard Karls University [Tübingen, Germany], Université Grenoble Alpes (UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Grenoble, Hammersmith Hospital NHS Imperial College Healthcare, Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Institució Catalana de Recerca i Estudis Avançats (ICREA), Pfister, Dominik [0000-0002-0542-2638], Núñez, Nicolás Gonzalo [0000-0003-3837-270X], Govaere, Olivier [0000-0002-4426-6930], Szydlowska, Marta [0000-0002-4660-899X], Gupta, Revant [0000-0002-0881-5074], Deczkowska, Aleksandra [0000-0003-0844-4346], Friebel, Ekaterina [0000-0003-1419-2376], Lenggenhager, Daniela [0000-0002-5382-9854], Moncsek, Anja [0000-0002-1191-5842], Inverso, Donato [0000-0003-0987-3345], Vacca, Michele [0000-0002-1973-224X], Marra, Fabio [0000-0001-8629-0878], Allison, Michael [0000-0003-3677-3294], D'Alessio, Antonio [0000-0002-9164-3671], Personeni, Nicola [0000-0002-7995-272X], Rimassa, Lorenza [0000-0001-9957-3615], Pomej, Katharina [0000-0002-2807-3565], Peck-Radosavljevic, Markus [0000-0002-0597-2728], Mallm, Jan-Philipp [0000-0002-7059-4030], Schietinger, Andrea [0000-0003-3644-1687], Augustin, Hellmut G [0000-0002-7173-4242], Kikuchi, Hiroto [0000-0002-3601-8435], Duda, Dan G [0000-0001-7065-8797], Mei, Henrik E [0000-0003-0697-7755], Schulz, Axel Ronald [0000-0002-5106-0148], Ringelhan, Marc [0000-0003-3131-5657], Lujambio, Amaia [0000-0002-2798-1481], Dufour, Jean-Francois [0000-0002-8062-1346], Kudo, Masatoshi [0000-0002-4102-3474], Djouder, Nabil [0000-0001-8423-1030], Zender, Lars [0000-0001-7626-2849], Pinato, David J [0000-0002-3529-0103], Rad, Roland [0000-0002-6849-9659], Mertens, Joachim C [0000-0003-2007-0308], Weber, Achim [0000-0003-0073-3637], Meissner, Felix [0000-0003-1000-7989], Amit, Ido [0000-0003-2968-877X], Knolle, Percy [0000-0003-2983-0414], Becher, Burkhard [0000-0002-1541-7867], Llovet, Josep M [0000-0003-0547-2667], Heikenwalder, Mathias [0000-0002-3135-2274], Apollo - University of Cambridge Repository, Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry (MPIB), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz Zentrum München = German Research Center for Environmental Health, Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Firenze = University of Florence (UniFI), MARCHE, Patrice, D’Alessio, Antonio [0000-0002-9164-3671], Augustin, Hellmut G. [0000-0002-7173-4242], Duda, Dan G. [0000-0001-7065-8797], Mei, Henrik E. [0000-0003-0697-7755], Pinato, David J. [0000-0002-3529-0103], Mertens, Joachim C. [0000-0003-2007-0308], and Llovet, Josep M. [0000-0003-0547-2667]

Subjects
Male, Carcinogenesis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, B7-H1 Antigen, 13/2, 13/1, Mice, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, LIVER-CANCER, R PACKAGE, RNA-SEQ, 14/19, Cancer, 0303 health sciences, Multidisciplinary, NONALCOHOLIC STEATOHEPATITIS, Liver Neoplasms, article, ddc, 3. Good health, 13/31, Multidisciplinary Sciences, medicine.anatomical_structure, Liver, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Disease Progression, Science & Technology - Other Topics, [SDV.IMM]Life Sciences [q-bio]/Immunology, 64/60, Tumor necrosis factor alpha, Immunotherapy, Adjuvant, 631/67, Carcinoma, Hepatocellular, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, 610 Medicine & health, [SDV.CAN]Life Sciences [q-bio]/Cancer, 14/32, 03 medical and health sciences, 14/34, 13/21, [SDV.CAN] Life Sciences [q-bio]/Cancer, ADVANCED HEPATOCELLULAR-CARCINOMA, NAFLD, medicine, Animals, Humans, 14/35, 030304 developmental biology, Science & Technology, Tumor Necrosis Factor-alpha, business.industry, 631/250/251, medicine.disease, PHASE-III, digestive system diseases, 13/51, 14/63, 59/57, T-CELLS, Cancer research, Steatohepatitis, business, CD8
Abstract

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment., In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.

Published
2021

132. Quantitative Proteomics of Secreted Proteins.

Author

Frauenstein A and Meissner F

Subjects
Humans, Chromatography, Liquid methods, Proteins metabolism, Proteomics methods, Tandem Mass Spectrometry methods
Abstract

Secreted proteins such as cytokines, interleukins, growth factors, and hormones have pleiotropic functions and facilitate intercellular communication in organisms. Quantification of these proteins conventionally relies on antibody-based methods, i.e., enzyme-linked immunosorbent assays (ELISA), whose large-scale use is limited by availability, specificity, and affordability.Here, we describe an experimental and bioinformatics workflow to comprehensively quantify cellular protein secretion by mass spectrometry. Secreted proteins are collected in vitro or ex vivo, digested with proteases and the resulting peptide mixtures are analyzed in single liquid chromatography-mass spectrometry (LC-MS/MS) runs. Label-free quantification and bioinformatics analysis is conducted in the MaxQuant and Perseus computational environment. Our workflow allows the quantification of thousands of secreted proteins spanning a concentration range of four orders of magnitude and permits the systems-level characterization of secretory programs as well as the discovery of proteins with unexpected extracellular functions.

Published
2018
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133. Evidence of Extrapancreatic Glucagon Secretion in Man.

Author

Lund A, Bagger JI, Wewer Albrechtsen NJ, Christensen M, Grøndahl M, Hartmann B, Mathiesen ER, Hansen CP, Storkholm JH, van Hall G, Rehfeld JF, Hornburg D, Meissner F, Mann M, Larsen S, Holst JJ, Vilsbøll T, and Knop FK

Subjects
Aged, Blood Glucose metabolism, Case-Control Studies, Cholecystokinin metabolism, Chromatography, Liquid, Enzyme-Linked Immunosorbent Assay, Female, Gastric Inhibitory Polypeptide metabolism, Gastrins metabolism, Gastrointestinal Tract drug effects, Glucagon-Like Peptide 1 metabolism, Glucagon-Secreting Cells metabolism, Glucose pharmacology, Glucose Tolerance Test, Humans, Male, Middle Aged, Peptide Fragments metabolism, Proteomics, Radioimmunoassay, Tandem Mass Spectrometry, Gastrointestinal Tract metabolism, Glucagon metabolism, Pancreatectomy, Pancreatic Neoplasms surgery, Pancreatitis surgery
Abstract

Glucagon is believed to be a pancreas-specific hormone, and hyperglucagonemia has been shown to contribute significantly to the hyperglycemic state of patients with diabetes. This hyperglucagonemia has been thought to arise from α-cell insensitivity to suppressive effects of glucose and insulin combined with reduced insulin secretion. We hypothesized that postabsorptive hyperglucagonemia represents a gut-dependent phenomenon and subjected 10 totally pancreatectomized patients and 10 healthy control subjects to a 75-g oral glucose tolerance test and a corresponding isoglycemic intravenous glucose infusion. We applied novel analytical methods of plasma glucagon (sandwich ELISA and mass spectrometry-based proteomics) and show that 29-amino acid glucagon circulates in patients without a pancreas and that glucose stimulation of the gastrointestinal tract elicits significant hyperglucagonemia in these patients. These findings emphasize the existence of extrapancreatic glucagon (perhaps originating from the gut) in man and suggest that it may play a role in diabetes secondary to total pancreatectomy., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Published
2016
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