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CXCR2 inhibition enables NASH-HCC immunotherapy

Lookup NU author(s): Dr Jack LeslieORCiD, Erik Ramon Gil, Kathryn Gilroy, Dr Saimir Luli, Maja Laszczewska, Dr Catherine WilloughbyORCiD, Amy Collins, Dr Daniel Geh, Andrew Fuller, Dr David McDonald, Dr Gill Hulme, Dr Andrew Filby, Misti McCainORCiD, Professor Helen Reeves, Professor Derek Mann

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. 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.


Publication metadata

Author(s): Leslie J, Mackey JBG, Jamieson T, Ramon-Gil E, Drake TM, Fercoq F, Clark W, Gilroy K, Hedley A, Nixon C, Luli S, Laszczewska M, Pinyol R, Esteban-Fabro R, Willoughby CE, Haber PK, Andreu-Oller C, Rahbari M, Fan C, Pfister D, Raman S, Wilson N, Muller M, Collins A, Geh D, Fuller A, Mcdonald D, Hulme G, Filby A, Cortes-Lavaud X, Mohamed N-E, Ford CA, Raffo Iraolagoitia XL, Mcfarlane AJ, Mccain MV, Ridgway RA, Roberts EW, Barry ST, Graham GJ, Heikenwalder M, Reeves HL, Llovet JM, Carlin LM, Bird TG, Sansom OJ, Mann DA

Publication type: Article

Publication status: Published

Journal: Gut

Year: 2022

Pages: Epub ahead of print

Online publication date: 27/04/2022

Acceptance date: 17/03/2022

Date deposited: 06/06/2022

ISSN (print): 0017-5749

ISSN (electronic): 1468-3288

Publisher: BMJ Publishing Group

URL: https://doi.org/10.1136/gutjnl-2021-326259

DOI: 10.1136/gutjnl-2021-326259

PubMed id: 35477863


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