Immature neutrophils bring anti-PD-1 therapy in NASH-HCC to maturity
Menée à l'aide de modèles murins de carcinome hépatocellulaire lié à une stéatohépatite non alcoolique, cette étude met en évidence l'intérêt d'inhiber le récepteur CXCR2 des neutrophiles ayant infiltré la tumeur pour sensibiliser les cellules cancéreuses aux inhibiteurs de points de contrôle immunitaires
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 ICI treatment (ie, anti-PD-1), …
Gut 2022