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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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
27 April 2022
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| 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 
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| 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 |
| 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. |
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| Beschreibung: | Gesehen am 15.07.2024 |
| Beschreibung: | Online Resource |
| ISSN: | 1468-3288 |
| DOI: | 10.1136/gutjnl-2021-326259 |