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CXCR2 inhibition enables NASH-HCC immunotherapy

Leslie, Jack, Mackey, John B G, Jamieson, Thomas, Ramon-Gil, Erik, Drake, Thomas M, Fercoq, Frédéric, Clark, William, Gilroy, Kathryn, Hedley, Ann, Nixon, Colin, Luli, Saimir, Laszczewska, Maja, Pinyol, Roser, Esteban-Fabró, Roger, Willoughby, Catherine E, Haber, Philipp K, Andreu-Oller, Carmen, Rahbari, Mohammad, Fan, Chaofan, Pfister, Dominik, Raman, Shreya, Wilson, Niall, Müller, Miryam, Collins, Amy, Geh, Daniel, Fuller, Andrew, McDonald, David, Hulme, Gillian, Filby, Andrew, Cortes-Lavaud, Xabier, Mohamed, Noha-Ehssan, Ford, Catriona A, Raffo Iraolagoitia, Ximena L, McFarlane, Amanda J, McCain, Misti V, Ridgway, Rachel A, Roberts, Edward W, Barry, Simon T, Graham, Gerard J, Heikenwälder, Mathias, Reeves, Helen L, Llovet, Josep M, Carlin, Leo M, Bird, Thomas G, Sansom, Owen J and Mann, Derek A (2022) CXCR2 inhibition enables NASH-HCC immunotherapy. Gut, 71 (10). pp. 2093-2106. ISSN 0017-5749

Item Type: Article

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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More Information

Depositing User: Shreya Raman

Identifiers

Item ID: 19030
Identification Number: https://doi.org/10.1136/gutjnl-2021-326259
ISSN: 0017-5749
URI: http://sure.sunderland.ac.uk/id/eprint/19030
Official URL: http://dx.doi.org/10.1136/gutjnl-2021-326259

Users with ORCIDS

ORCID for Shreya Raman: ORCID iD orcid.org/0009-0006-8915-8286

Catalogue record

Date Deposited: 07 May 2025 09:49
Last Modified: 07 May 2025 09:49

Contributors

Author: Shreya Raman ORCID iD
Author: Jack Leslie
Author: John B G Mackey
Author: Thomas Jamieson
Author: Erik Ramon-Gil
Author: Thomas M Drake
Author: Frédéric Fercoq
Author: William Clark
Author: Kathryn Gilroy
Author: Ann Hedley
Author: Colin Nixon
Author: Saimir Luli
Author: Maja Laszczewska
Author: Roser Pinyol
Author: Roger Esteban-Fabró
Author: Catherine E Willoughby
Author: Philipp K Haber
Author: Carmen Andreu-Oller
Author: Mohammad Rahbari
Author: Chaofan Fan
Author: Dominik Pfister
Author: Niall Wilson
Author: Miryam Müller
Author: Amy Collins
Author: Daniel Geh
Author: Andrew Fuller
Author: David McDonald
Author: Gillian Hulme
Author: Andrew Filby
Author: Xabier Cortes-Lavaud
Author: Noha-Ehssan Mohamed
Author: Catriona A Ford
Author: Ximena L Raffo Iraolagoitia
Author: Amanda J McFarlane
Author: Misti V McCain
Author: Rachel A Ridgway
Author: Edward W Roberts
Author: Simon T Barry
Author: Gerard J Graham
Author: Mathias Heikenwälder
Author: Helen L Reeves
Author: Josep M Llovet
Author: Leo M Carlin
Author: Thomas G Bird
Author: Owen J Sansom
Author: Derek A Mann

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine

Subjects

Sciences > Health Sciences
Sciences

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