Inflammatory processes involved in NASH-related hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. In the recent years nonalcoholic fatty liver disease (NAFLD) is becoming a growing cause of HCCs and the incidence of NAFLD-related HCCs is expected to further dramatically increase by the next decade. Chronic inflammation is regarded as the driving force of NAFLD progression and a key factor in hepatic carcinogenesis. Hepatic inflammation in NAFLD results from the persistent stimulation of innate immunity in response to hepatocellular injury and gut dysbiosis as well as by the activation of adaptive immunity. However, the relative roles of innate and adaptive immunity in the processes leading to HCC are still incompletely characterized. This is due to the complex interplay between different liver cell populations, which is also strongly influenced by gut-derived bacterial products, metabolic/nutritional signals. Furthermore, carcinogenic mechanisms in NAFLD/NASH appear to involve the activation of signals mediated by hypoxia inducible factors. This review discusses recent data regarding the contribution of different inflammatory cells to NAFLD-related HCC and their possible impact on patient response to current treatments.

Keywords: Hepatocellular carcinoma; Liver inflammation; Nonalcoholic steatohepatitis; lymphocytes.

Figure 1. Contribution of immune/inflammatory cells to immune elusion by NASH-related HCC

NASH-associated HCC immune landscape is characterized by the expansion of cellular pools displaying potent immunosuppressive activities such as monocytic and polymorphonuclear myeloid-derived suppressor cells (M- and PMN-MDSCs), tumor-associated neutrophils (TANs), activated platelets, immunosuppressive TREM-2⁺ macrophages, regulatory T-cells, and IgA⁺/PDL-1⁺ plasma cells. Overall, these cell subsets contribute to limiting cancer immune surveillance by producing large amounts of immunomodulant mediators such as transforming growth factor-β1 (TGF-β1) and interleukin (IL)-10 that, in their turn, counteract effector T-cell functions. NASH-related HCC stands out for the accumulation of unconventional activated CD4⁺/ICOS⁺/PD-1⁺ T-cells and exhausted CD8⁺/PD1⁺ probably resulting from chronic antigen stimulation involving oxidative stress-derived epitopes (OSEs) and damage- and pathogen-associated molecular patterns (DAMPs and PAMPs) among others. The transition from NASH to HCC is also associated with the progressive development of dysfunctional NK/NKT cells showing impaired cytotoxic activity toward cancer cells.

Figure 2. Contribution of chronic inflammation, metabolic imbalances, and hypoxia in reshaping the immune landscape in NASH-related HCC

The transition from NASH to HCC is a complex process involving multiple factors such as lipotoxicity, oxidative stress, gut dysbiosis metabolic imbalances, chronic injury, and hypoxia that, in turn, stimulate chronic inflammation causing tissue scarring, and HCC development. Chronic inflammation, hypoxia and metabolic imbalances also induce a profound reprogramming of the immune system that results in the loss of its antitumour action, thus leading to a cancer-prone microenvironment in which malignant cells can proliferate undisturbed.