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

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