Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by an enhanced activation of the immune system, which predispose the evolution to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Resident macrophages and leukocytes exert a key role in the pathogenesis of NAFLD. In particular, CD4+ effector T cells are activated during the early stages of liver inflammation and are followed by the increase of natural killer T cells and of CD8+ T cytotoxic lymphocytes which contribute to auto-aggressive tissue damage. To counteract T cells activation, programmed cell death 1 (PD-1) and its ligand PDL-1 are exposed respectively on lymphocytes and liver cells’ surface and can be targeted for therapy by using specific monoclonal antibodies, such as of Nivolumab, Pembrolizumab, and Atezolizumab. Despite the combination of Atezolizumab and Bevacizumab has been approved for the treatment of advanced HCC, PD-1/PD-L1 blockage treatment has not been approved for NAFLD and adjuvant immunotherapy does not seem to improve survival of patients with early-stage HCC. In this regard, different ongoing phase III trials are testing the efficacy of anti-PD-1/PD-L1 antibodies in HCC patients as first line therapy and in combination with other treatments. However, in the context of NAFLD, immune checkpoints inhibitors may not improve HCC prognosis, even worse leading to an increase of CD8+PD-1+ T cells and effector cytokines which aggravate liver damage. Here, we will describe the main pathogenetic mechanisms which characterize the immune system involvement in NAFLD discussing advantages and obstacles of anti PD-1/PDL-1 immunotherapy.
Highlights
Therapy in Non-alcoholic fatty liver disease (NAFLD): Advantages and Obstacles in the Treatment of Advanced Disease
NAFLD is usually a mild disease characterized by simple steatosis; it may progress to more severe forms where inflammation and fibrosis occur, possibly evolving to cirrhosis and hepatocellular carcinoma (HCC) [2]
Both data on experimental models and patients confirmed the crucial role of the immune system and inflammatory pathways in the pathogenesis and progression of NAFLD to advanced disease and HCC
Summary
Non-alcoholic fatty liver disease (NAFLD) is the commonest chronic liver disorder in Western countries and is defined by fat accumulation in more than 5% of hepatocytes in the absence of other causes of liver diseases [1]. Both genetic and epigenetic factors predispose to NAFLD and its advanced forms, including HCC [6,7]. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) competes with CD28 for binding of B7 molecules and results in a net negative signal for the proliferation and the survival of the T cell [10,11]. In this regard, if on the one hand a hyperactivated immune system contributes to progression from steatosis to NASH and fibrosis, on the other hand when downregulated, it favors hepatic carcinogenesis due to insufficient tumor surveillance. This review aims to describe the main pathogenetic mechanisms by which the immune system fosters the development of NAFLD and its progression to advanced forms including HCC, dealing with the immune therapeutic applications of PD-1/PD-L1 target therapy
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