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Immature neutrophils bring anti-PD-1 therapy in NASH-HCC to maturity
  1. Michael Dudek1,
  2. Frank Tacke2
  1. 1 Institute of Molecular Immunology & Experimental Oncology, Technical University of Munich Hospital Rechts der Isar, Munchen, Germany
  2. 2 Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany
  1. Correspondence to Professor Frank Tacke, Department of Hepatology & Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Berlin, Germany; frank.tacke{at}

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Liver cancer remains a global health burden, and hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancer cases. HCC can have viral causes, for example, chronic hepatitis B virus or hepatitis C virus infections, and non-viral causes such as non-alcoholic steatohepatitis (NASH) or alcohol-related liver cirrhosis. Particularly HCC related to NASH increased tremendously over the past decade and is expected to rise further. NASH, the advanced form of non-alcoholic fatty liver diseases (NAFLD), is characterised by chronic liver inflammation as a consequence of lipid accumulation and metabolic injury in the liver. This inflammatory hepatic environment in NASH is critical for driving HCC, so that HCC can even develop in non-cirrhotic NASH livers.1 The introduction of immune checkpoint inhibition (ICI) as the new first-line systemic therapy for HCC has raised substantial concerns whether ‘T-cell activation’ with ICI as part of the tumour defence would be similarly efficacious in NASH-related versus viral induced HCC.2 In fact, a recent meta-analysis had indicated reduced efficacy of ICI-based regimen in NASH-HCC, possibly related to the unique immune environment in NASH-HCC livers which is characterised by a combined immunosuppressive and pro-inflammatory milieu.3 In these livers, not only exhausted tumour-specific PD-1+CD8 T cells exist but also tissue-damaging, autoaggressive CXCR6+PD-1+ CD8 T cells, which explains why PD-1 therapy might also have tumour-promoting effects in NASH-induced HCC.4 5 Clearly, optimised immunotherapy in NASH-induced HCC is required to specifically reinvigorate tumour-specific CD8 T cells to promote anti-tumour immunity.

In this issue of Gut, Leslie et al highlight tumour-associated neutrophils (TANs) as a potential mechanistic contributor as well as a potential therapeutic target in NASH-HCC.5 They demonstrated that in preclinical NASH-HCC mouse models, which respond poorly to …

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  • Correction notice This article has been corrected since it published Online First. A duplicated sentence has been removed.

  • Contributors FT and MD equally contributed to the commentary for Leslie et al.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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