CXCR2 inhibition enables NASH-HCC immunotherapy

Jack Leslie, John B.G. 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 PfisterShreya 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

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

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.

Original languageEnglish
Pages (from-to)2093-2106
Number of pages14
JournalGut
Volume71
Issue number10
DOIs
StatePublished - 1 Oct 2022

Keywords

  • hepatocellular carcinoma
  • immunotherapy
  • nonalcoholic steatohepatitis

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