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| Verfasst von: | Leslie, Jack [VerfasserIn]  |
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| | Mackey, John B. G. [VerfasserIn] |
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| | Jamieson, Thomas [VerfasserIn] |
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| | Ramon-Gil, Erik [VerfasserIn] |
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| | Drake, Thomas M. [VerfasserIn] |
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| | Fercoq, Frédéric [VerfasserIn] |
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| | Clark, William [VerfasserIn] |
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| | Gilroy, Kathryn [VerfasserIn] |
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| | Hedley, Ann [VerfasserIn] |
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| | Nixon, Colin [VerfasserIn] |
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| | Luli, Saimir [VerfasserIn] |
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| | Laszczewska, Maja [VerfasserIn] |
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| | Pinyol, Roser [VerfasserIn] |
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| | Esteban-Fabró, Roger [VerfasserIn] |
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| | Willoughby, Catherine E. [VerfasserIn] |
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| | Haber, Philipp K. [VerfasserIn] |
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| | Andreu-Oller, Carmen [VerfasserIn] |
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| | Rahbari, Mohammad [VerfasserIn] |
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| | Fan, Chaofan [VerfasserIn] |
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| | Pfister, Dominik [VerfasserIn] |
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| | Raman, Shreya [VerfasserIn] |
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| | Wilson, Niall [VerfasserIn] |
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| | Müller, Miryam [VerfasserIn] |
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| | Collins, Amy [VerfasserIn] |
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| | Geh, Daniel [VerfasserIn] |
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| | Fuller, Andrew [VerfasserIn] |
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| | McDonald, David [VerfasserIn] |
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| | Hulme, Gillian [VerfasserIn] |
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| | Filby, Andrew [VerfasserIn] |
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| | Cortes-Lavaud, Xabier [VerfasserIn] |
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| | Mohamed, Noha-Ehssan [VerfasserIn] |
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| | Ford, Catriona A. [VerfasserIn] |
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| | Iraolagoitia, Ximena L. Raffo [VerfasserIn] |
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| | McFarlane, Amanda J. [VerfasserIn] |
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| | McCain, Misti V. [VerfasserIn] |
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| | Ridgway, Rachel A. [VerfasserIn] |
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| | Roberts, Edward W. [VerfasserIn] |
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| | Barry, Simon T. [VerfasserIn] |
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| | Graham, Gerard J. [VerfasserIn] |
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| | Heikenwälder, Mathias [VerfasserIn] |
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| | Reeves, Helen L. [VerfasserIn] |
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| | Llovet, Josep M. [VerfasserIn] |
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| | Carlin, Leo M. [VerfasserIn] |
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| | Bird, Thomas G. [VerfasserIn] |
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| | Sansom, Owen J. [VerfasserIn] |
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| | Mann, Derek A. [VerfasserIn] |
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| Titel: | CXCR2 inhibition enables NASH-HCC immunotherapy |
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| Verf.angabe: | Jack Leslie, John BG Mackey, Thomas Jamieson, Erik Ramon-Gil, Thomas M Drake, Frédéric Fercoq, William Clark, Kathryn Gilroy, Ann Hedley, Colin Nixon, Saimir Luli, Maja Laszczewska, Roser Pinyol, Roger Esteban-Fabró, Catherine E Willoughby, Philipp K Haber, Carmen Andreu-Oller, Mohammad Rahbari, Chaofan Fan, Dominik Pfister, Shreya Raman, Niall Wilson, Miryam Müller, Amy Collins, Daniel Geh, Andrew Fuller, David McDonald, Gillian Hulme, Andrew Filby, Xabier Cortes-Lavaud, Noha-Ehssan Mohamed, Catriona A Ford, Ximena L Raffo Iraolagoitia, Amanda J McFarlane, Misti V McCain, Rachel A Ridgway, Edward W Roberts, Simon T Barry, Gerard J Graham, Mathias Heikenwälder, Helen L Reeves, Josep M Llovet, Leo M Carlin, Thomas G Bird, Owen J Sansom, Derek A Mann |
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| E-Jahr: | 2022 |
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| Jahr: | 27 April 2022 |
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| Umfang: | 14 S. |
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| Fussnoten: | Gesehen am 15.07.2024 |
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| Titel Quelle: | Enthalten in: Gut |
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| Ort Quelle: | London : BMJ Publishing Group, 1960 |
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| Jahr Quelle: | 2022 |
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| Band/Heft Quelle: | 71(2022), 10, Seite 2093-2106 |
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| ISSN Quelle: | 1468-3288 |
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| Abstract: | Objective Hepatocellular carcinoma (HCC) is increasingly associated with non-alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor may sensitise NASH-HCC to ICI therapy. - Design Neutrophil infiltration was characterised in human HCC and mouse models of HCC. Late-stage intervention with anti-PD1 and/or a CXCR2 inhibitor was performed in murine models of NASH-HCC. The tumour immune microenvironment was characterised by imaging mass cytometry, RNA-seq and flow cytometry. - Results Neutrophils expressing CXCR2, a receptor crucial to neutrophil recruitment in acute-injury, are highly represented in human NASH-HCC. In models of NASH-HCC lacking response to ICI, the combination of a CXCR2 antagonist with anti-PD1 suppressed tumour burden and extended survival. Combination therapy increased intratumoural XCR1+ dendritic cell activation and CD8+ T cell numbers which are associated with anti-tumoural immunity, this was confirmed by loss of therapeutic effect on genetic impairment of myeloid cell recruitment, neutralisation of the XCR1-ligand XCL1 or depletion of CD8+ T cells. Therapeutic benefit was accompanied by an unexpected increase in tumour-associated neutrophils (TANs) which switched from a protumour to anti-tumour progenitor-like neutrophil phenotype. Reprogrammed TANs were found in direct contact with CD8+ T cells in clusters that were enriched for the cytotoxic anti-tumoural protease granzyme B. Neutrophil reprogramming was not observed in the circulation indicative of the combination therapy selectively influencing TANs. - Conclusion CXCR2-inhibition induces reprogramming of the tumour immune microenvironment that promotes ICI in NASH-HCC. |
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| DOI: | doi:10.1136/gutjnl-2021-326259 |
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| URL: | Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.
Volltext: https://doi.org/10.1136/gutjnl-2021-326259 |
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| | Volltext: https://gut.bmj.com/content/71/10/2093 |
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| | DOI: https://doi.org/10.1136/gutjnl-2021-326259 |
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| Datenträger: | Online-Ressource |
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| Sprache: | eng |
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| Sach-SW: | hepatocellular carcinoma |
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| | immunotherapy |
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| | nonalcoholic steatohepatitis |
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| K10plus-PPN: | 1895386543 |
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| Verknüpfungen: | → Zeitschrift |
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CXCR2 inhibition enables NASH-HCC immunotherapy / Leslie, Jack [VerfasserIn]; 27 April 2022 (Online-Ressource)
