Buchumschlag

CXCR2 inhibition enables NASH-HCC immunotherapy

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 neutr...

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Bibliographische Detailangaben
Hauptverfasser: Leslie, Jack (VerfasserIn) , Mackey, John B. G. (VerfasserIn) , Jamieson, Thomas (VerfasserIn) , Ramon-Gil, Erik (VerfasserIn) , Drake, Thomas M. (VerfasserIn) , Fercoq, Frédéric (VerfasserIn) , Clark, William (VerfasserIn) , Gilroy, Kathryn (VerfasserIn) , Hedley, Ann (VerfasserIn) , Nixon, Colin (VerfasserIn) , Luli, Saimir (VerfasserIn) , Laszczewska, Maja (VerfasserIn) , Pinyol, Roser (VerfasserIn) , Esteban-Fabró, Roger (VerfasserIn) , Willoughby, Catherine E. (VerfasserIn) , Haber, Philipp K. (VerfasserIn) , Andreu-Oller, Carmen (VerfasserIn) , Rahbari, Mohammad (VerfasserIn) , Fan, Chaofan (VerfasserIn) , Pfister, Dominik (VerfasserIn) , Raman, Shreya (VerfasserIn) , Wilson, Niall (VerfasserIn) , Müller, Miryam (VerfasserIn) , Collins, Amy (VerfasserIn) , Geh, Daniel (VerfasserIn) , Fuller, Andrew (VerfasserIn) , McDonald, David (VerfasserIn) , Hulme, Gillian (VerfasserIn) , Filby, Andrew (VerfasserIn) , Cortes-Lavaud, Xabier (VerfasserIn) , Mohamed, Noha-Ehssan (VerfasserIn) , Ford, Catriona A. (VerfasserIn) , Iraolagoitia, Ximena L. Raffo (VerfasserIn) , McFarlane, Amanda J. (VerfasserIn) , McCain, Misti V. (VerfasserIn) , Ridgway, Rachel A. (VerfasserIn) , Roberts, Edward W. (VerfasserIn) , Barry, Simon T. (VerfasserIn) , Graham, Gerard J. (VerfasserIn) , Heikenwälder, Mathias (VerfasserIn) , Reeves, Helen L. (VerfasserIn) , Llovet, Josep M. (VerfasserIn) , Carlin, Leo M. (VerfasserIn) , Bird, Thomas G. (VerfasserIn) , Sansom, Owen J. (VerfasserIn) , Mann, Derek A. (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 27 April 2022
In: Gut
Year: 2022, Jahrgang: 71, Heft: 10, Pages: 2093-2106
ISSN:1468-3288
DOI:10.1136/gutjnl-2021-326259
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1136/gutjnl-2021-326259
Verlag, lizenzpflichtig, Volltext: https://gut.bmj.com/content/71/10/2093
Volltext
Verfasserangaben: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
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 15.07.2024
Beschreibung:Online Resource
ISSN:1468-3288
DOI:10.1136/gutjnl-2021-326259

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