CXCR2 inhibition enables NASH-HCC immunotherapy

Leslie, J. et al. (2022) CXCR2 inhibition enables NASH-HCC immunotherapy. Gut, (doi: 10.1136/gutjnl-2021-326259) (PMID:35477863) (Early Online Publication)

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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.

Item Type:Articles
Keywords:GI cancer, 1506, 2312, hepatocellular carcinoma, immunotherapy, nonalcoholic steatohepatitis.
Status:Early Online Publication
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ridgway, Dr Rachel and Carlin, Dr Leo and Clark, Mr William and Ford, Miss Catriona and Jamieson, Mr Thomas and Drake, Dr Thomas and Sansom, Professor Owen and Graham, Professor Gerard and Mackey, John and Bird, Dr Thomas and Nixon, Mr Colin and Roberts, Dr Edward and Gilroy, Dr Kathryn
Authors: Leslie, J., Mackey, J. B.G., Jamieson, T., Ramon-Gil, E., Drake, T. M., Fercoq, F., Clark, W., Gilroy, K., Hedley, A., Nixon, C., Luli, S., Laszczewska, M., Pinyol, R., Esteban-Fabró, R., Willoughby, C. E., Haber, P. K., Andreu-Oller, C., Rahbari, M., Fan, C., Pfister, D., Raman, S., Wilson, N., Müller, M., Collins, A., Geh, D., Fuller, A., McDonald, D., Hulme, G., Filby, A., Cortes-Lavaud, X., Mohamed, N.-E., Ford, C. A., Raffo Iraolagoitia, X. L., McFarlane, A. J., McCain, M. V., Ridgway, R. A., Roberts, E. W., Barry, S. T., Graham, G. J., Heikenwälder, M., Reeves, H. L., Llovet, J. M., Carlin, L. M., Bird, T. G., Sansom, O. J., and Mann, D. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Gut
Publisher:BMJ Publishing Group
ISSN:0017-5749
ISSN (Online):1468-3288
Published Online:27 April 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Gut 2022
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301496HUNTER: Hepatocellular Carcinoma Expediter NetworkThomas BirdCancer Research UK (CRUK)BH172934 - C9380/A26813CS - Experimental Therapeutics