Highlights
- •Multiple murine models of NASH-HCC show CD8+ T-cell-dependent resistance to ICI therapy.
- •Correlative transcriptomic analysis of hepatic CD8+ T cells revealed NASH-induced mitochondrial aberrations.
- •Although hepatic CD8+ T cells are activated in NASH mice, they have impaired motility and mitochondrial fitness.
- •NASH may diminish the efficacy of ICI therapy in patients with HCC.
- •Metformin can salvage ICI therapy and CD8+ T-cell activity in tumour-bearing NASH mice.
Background & Aims
Non-alcoholic steatohepatitis (NASH) represents the fastest growing underlying cause
of hepatocellular carcinoma (HCC) and has been shown to impact immune effector cell
function. The standard of care for the treatment of advanced HCC is immune checkpoint
inhibitor (ICI) therapy, yet NASH may negatively affect the efficacy of ICI therapy
in HCC. The immunologic mechanisms underlying the impact of NASH on ICI therapy remain
unclear.
Methods
Herein, using multiple murine NASH models, we analysed the influence of NASH on the
CD8+ T-cell-dependent anti-PD-1 responses against liver cancer. We characterised CD8+ T cells’ transcriptomic, functional, and motility changes in mice receiving a normal
diet (ND) or a NASH diet.
Results
NASH blunted the effect of anti-PD-1 therapy against liver cancers in multiple murine
models. NASH caused a proinflammatory phenotypic change of hepatic CD8+ T cells. Transcriptomic analysis revealed changes related to NASH-dependent impairment
of hepatic CD8+ T-cell metabolism. In vivo imaging analysis showed reduced motility of intratumoural CD8+ T cells. Metformin treatment rescued the efficacy of anti-PD-1 therapy against liver
tumours in NASH.
Conclusions
We discovered that CD8+ T-cell metabolism is critically altered in the context of
NASH-related liver cancer, impacting the effectiveness of ICI therapy – a finding
which has therapeutic implications in patients with NASH-related liver cancer.
Lay summary
Non-alcoholic steatohepatitis represents the fastest growing cause of hepatocellular
carcinoma. It is also associated with reduced efficacy of immunotherapy, which is
the standard of care for advanced hepatocellular carcinoma. Herein, we show that non-alcoholic
steatohepatitis is associated with impaired motility, metabolic function, and response
to anti-PD-1 treatment in hepatic CD8+ T cells, which can be rescued by metformin treatment.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: March 31, 2022
Accepted:
March 3,
2022
Received in revised form:
February 8,
2022
Received:
November 4,
2021
Identification
Copyright
Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
