期刊
GUT
卷 71, 期 10, 页码 2093-2106出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2021-326259
关键词
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资金
- CRUK [C9380/A26813]
- MRC program [MR/K0019494/1, MR/R023026/1]
- CRUK programme grant [C18342/A23390]
- CRUK grant [CRUK A23983, CRUK A21339]
- Wellcome Trust [WT107492Z]
- CRUK Newcastle Experimental Cancer Medicine Centre award [C9380/A18084]
- CRUK core funding [A17196, A31287]
- Faculty of Medical Sciences, Newcatle University
- Newcastle CRUK Clinical Academic Training Programme
- MICINN/MINECO [BES-2017-081286]
- Fundacio Universitaria Agusti Pedro i Pons
- Sara Borrell fellowship from the Instituto de Salud Carlos III (ISCIII) [CD19/00109]
- European Social Fund
- German Research Foundation (DFG) [HA 8754/1-1]
- Fulbright Espana
- NIH [RO1DK56621, RO1DK128289]
- Samuel Waxman Cancer Research Foundation
- Spanish National Health Institute [PID2019-105378RB-I00]
- Cancer Research UK
- Fondazione AIRC
- Fundacion Cientifica de la Asociacion Espanola Contra el Cancer [C9380/A26813]
- Generalitat de Catalunya (AGAUR) [SGR-1358]
- WE Harker Foundation
This study found that targeting neutrophils using a CXCR2 small molecule inhibitor can enhance the sensitivity of non-alcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) to immune checkpoint inhibition therapy (ICI). The combination therapy can reprogram the tumor immune microenvironment, increase the number of anti-tumor immune cells, and improve treatment outcomes.
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.
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