CXCR2 inhibition enables NASH-HCC immunotherapy. Issue 10 (27th April 2022)

• Record Type: Journal Article
• Authors: 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; Mann, Derek A;
• Is Part Of: Gut. Volume 71:Issue 10(2022)
• Page Start: 2093
• Page End: 2106
• Publication Date: 2022-04-27
• Subjects: hepatocellular carcinoma -- immunotherapy -- nonalcoholic steatohepatitis; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2021-326259
• Languages: English
• ISSNs: 0017-5749

Abstract

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.