Journal Article

CXCR2 inhibition enables NASH-HCC immunotherapy

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

2022

Overview

ObjectiveHepatocellular 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.DesignNeutrophil 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.ResultsNeutrophils 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.ConclusionCXCR2-inhibition induces reprogramming of the tumour immune microenvironment that promotes ICI in NASH-HCC.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Animal models / Antigens / CD8 antigen / Cell activation / CXCR2 protein / Cytotoxicity / Dendritic cells / Fatty liver / Flow cytometry / Gene expression / Genotype & phenotype / Granzyme B / Hepatitis / Hepatocellular carcinoma / Hepatology / Immune checkpoint inhibitors / Immunotherapy / Leukocytes (neutrophilic) / Liver cancer / Lymphocytes / Lymphocytes T / Metastases / Microenvironments / Neutrophils / nonalcoholic steatohepatitis / PD-1 protein / Phenotypes / Tumors / Vascular endothelial growth factor