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Inflammation in Hepatocellular Carcinoma: Comparison
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Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Eduardo Bonavita.

Hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer, is prototypically an inflammation-driven cancer developing after years of inflammatory insults.

  • inflammation
  • tumor immunology
  • hepatocellular carcinoma

1. Introduction

The liver is a central organ performing vital functions related to metabolism, detoxification, digestion, and immunity. Because of its anatomy, the liver is continuously exposed to antigens of different origins. The portal vein drains blood from the intestine, spleen, and pancreas to the liver, carrying many foreign molecules derived from both food and the intestinal microbiota. The hepatic immune compartment is thus characterized by a delicate balance between tolerance toward harmless antigens and activation against potential pathogens. Tolerance in the liver is mediated by several non-parenchymal cells which comprise specialized antigen-presenting cells (APCs), such as dendritic cells (DCs), Kupffer cells (KCs), and other non-immune cells, such as liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells [1]. These cells act in concert and maintain a tolerogenic environment through the secretion of immunosuppressive factors, such as transforming growth factor (TGF)-β and interleukin (IL)-10, or via the expression of surface inhibitory ligands, such as programmed death (PD)-ligand-1 (PD-L1). However, this equilibrium can be perturbed by several factors, such as environmental or genetic conditions. Viral infections, metabolic syndrome, alcohol consumption, toxins, and genetic predispositions can lead to the excessive activation of the hepatic immune cells. The consequent inflammatory environment is deleterious for liver functions, and it is associated with an increased insurgence of cancer [2].
Alcohol-related liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are becoming the most frequent cause of chronic liver disorders. Notably, over the last ten years, both conditions have contributed to the occurrence of cirrhosis and HCC worldwide and have gradually overcome viral hepatitis infections as the leading cause of liver pathology [3,4][3][4]. Among the diverse factors contributing to these temporal trend shifts, modifications in the epidemiology of viral hepatitis, alcohol consumption, and a general increase in obesity and type 2 diabetes are the most common. Remarkably, these conditions share the ability to induce oxidative stress and hepatocellular death, which ultimately lead to exacerbated inflammatory conditions and disease progression. Chronic inflammation represents an essential trigger of carcinogenesis. However, in about 25% of the cases, NAFLD-related HCC can develop in absence of cirrhosis, unlike conditions such as viral infections or ALD [3,4][3][4]. Although a plethora of factors can influence liver diseases (e.g., genetic predisposition, lifestyle, and food habits), further fundamental and clinical studies are necessary to understand how different hepatic disorders affect cancer development and progression.
Primary liver cancer is the sixth most frequently diagnosed cancer and the third leading cause of cancer-related death worldwide. Among all the liver cancer types, HCC has the highest prevalence (75–85%) and mortality rate [5]. Unfortunately, most HCC patients are not eligible for curative treatment approaches, such as surgery or liver transplantation, as they often present an advanced disease at the time of diagnosis. The combination of the monoclonal antibodies bevacizumab and atezolizumab, targeting vascular endothelial growth factor (VEGF)-A and PD-L1, respectively, has become the standard of treatment for advanced HCC settings [6]. However, the response rate is still limited to 30% of patients, with a bias towards HCCs that are secondary to viral infections [7,8,9][7][8][9]. Indeed, the benefit of ICB therapy in non-viral related HCCs, such as those associated with non-alcoholic steatohepatitis (NASH), is still questionable [7]. Moreover, the safety of ICB drugs in liver cancer patients remains uncertain due to the high chance of immune-related hepatotoxicity and comorbidities associated with hepatic dysfunction [8,9][8][9].
A superior understanding of the immune landscape of the liver is essential for improving the efficacy and safety of immunotherapies based on ICB [10]. In addition to being a site of primary carcinogenesis, many cancer types have a high tropism for the liver, including colorectal, breast, kidney, lung, bladder, and melanoma. Additionally, cancer patients who develop liver metastasis have a dismal prognosis [11]. Mounting evidence suggests that cancer cells which invade or grow in the liver can promote immune tolerance by suppressing both local and systemic immunity [11]. Notably, recent studies exploring the role of secondary liver lesions in response to ICB demonstrated the limited efficacy of immunotherapy due to systemic immune suppression in patients with liver metastasis [11].

2. The Role of Inflammation in HCC Occurrence and Progression

Inflammation is a protective mechanism triggered by a damaging event that involves the recruitment of leukocytes, the production of soluble mediators, the remodeling of the extracellular matrix, and the activation of the complement system. From an evolutionary perspective, inflammation was positively selected due to its critical role in host defense against pathogens, tissue repair, regeneration, and, in general, tissue homeostasis. Tumors are inflamed tissues in which different types of inflammation can have opposing functions during the initiation and progression phases [12]. Inflammation as a result of the activation of the immune system against cancerous cells can facilitate elimination before tumor initiation through a process named immunosurveillance [13]. Conversely, the excessive and long-lasting activation of the immune responses, as in the case of chronic inflammatory diseases, can promote tumor outgrowth. Inflammatory signals enhance proliferation, immune cell recruitment, and polarization toward pro-tumorigenic phenotypes. In more advanced disease settings, specific tumor-cell-intrinsic properties can directly modulate antitumor immunity, thus favoring immune escape, cancer progression, and resistance to therapy [14]. In addition, inflammation influences the metastasis process in a wide range of aspects, from cell plasticity to migration and the awakening from a dormant metastatic seed [15]. Clinical evidence has shown that the inhibition of inflammation by non-steroidal anti-inflammatory drugs reduces the risk of cancer-related death in the long term [16]. The persistent immune pressure that actively eliminates the most immunogenic neoplastic cells can also enable the survival of cancer cells, which have acquired features to escape immune control. The result of this process is referred to as immunoediting and consists of the capacity of certain cancer cells to withstand anti-tumor immunity through the loss of tumor antigens, reduced sensitivity to immune effector mechanisms, or via the induction of an immunosuppressive and tolerogenic TME [13]. In a healthy liver, a tolerogenic environment is critical for maintaining homeostasis and preventing liver disease. Abnormal inflammatory conditions can alter the liver’s tolerance. Chronic infections (i.e., HCV and HBV infections), the release of damage-associated molecules (DAMPs) due to toxic liver damage (i.e., alcoholic steatohepatitis—ASH), or liver hereditary diseases (i.e., hemochromatosis) and fat accumulation (i.e., NASH) can disrupt the immune equilibrium of the liver. Moreover, these conditions contribute to the increased rate of death of the hepatocytes, causing an enhanced production of inflammatory cytokines and DAMPs with a consequent influx of activated immune cells, thereby compromising the physiological tolerance [17]. Chronic necroinflammation, consisting of continuous cellular death, compensatory regeneration, and the activation of non-parenchymal cells, is often associated with fibrosis. Proliferation causes replicative stress, DNA damage, and genetic instability, thus supporting the recruitment of immune cells such as the macrophages and neutrophils, which produce reactive oxygen and nitrogen species (ROS and RNS) and favor the accumulation of mutations. The cellular stress, combined with epigenetic modifications, mitochondrial alterations, and senescence, can lead to cancer [17]. Furthermore, inflammation-associated molecules can trigger the de-differentiation of post-mitotic epithelial cells into stem-like cells that have the potential to create tumors [18]. This complex combination of factors might explain the huge intra- and inter-tumor heterogeneity existing among different types of HCC [19]. About 15–20% of all cancers are secondary to a condition of chronic inflammation in the tissue of origin [20]. This frequency is increased to 90% in the case of HCC, which is often diagnosed after a condition of fibrosis and/or cirrhosis [21]. During cell death, hepatocytes release alarmins, such as IL-1α and high mobility group box 1 (HMGB1). These molecules induce the production of inflammatory mediators, such as IL-6, that promote the survival and proliferation of the transformed hepatocytes [22,23][22][23]. Both innate and adaptive immune cells are involved in this process. Macrophages and DCs can increase their number by local proliferation, differentiation, or the recruitment of precursors from the circulation, together with monocytes, neutrophils, and innate lymphoid cells (ILCs) [15]. In mouse models of NASH, the antibody-mediated depletion of CD8+ T cells abolishes liver damage, suggesting that the activation of cytotoxic lymphocytes (CTLs) is one of the main causes of hepatocyte death [24]. Another report demonstrated that the depletion of CD8+ T cells and the inhibition of lymphotoxin-B receptor significantly delay the development of tumors in mice affected by chronic liver injuries [25]. Furthermore, certain subsets of CD4+ T cells have shown pro-tumorigenic functions. For example, systemic IL-17A from Th17 cells induced neutrophil infiltration in the adipose tissue, worsening NASH through the release of fatty acids, as well as DNA damage in the hepatocytes and HCC [26]. However, during cancer progression, these cell subsets assume a critical anti-tumorigenic function. Large numbers of tumor-infiltrating CD8+ T cells are correlated with increased overall survival, long-term relapse-free survival, and slower tumor progression [25,27][25][27]. Additionally, in a murine model of NASH and HCC, the depletion of CD4+ T cells promoted tumor growth [28]. Innate immune cells carry out a central task in tumor development. In HCC, tumor-associated macrophages (TAMs) can produce cytokines to sustain tumor growth (i.e., IL-1β, TNF, IL-6), promote neo-angiogenesis via the VEGF pathway, and induce cytokine-mediated immunosuppression (i.e., IL 10, TGF-β). The heightened infiltration of TAMs and higher IL-1β serum levels have been associated with a poor prognosis in HCC patients with necrotic tumors. In this woresearkch, the authoresearchers showed that IL-1β induced the epithelial-to-mesenchymal transition of cancer cells through the hypoxia-inducible factor 1α (HIF-1α), thereby initiating the metastatic process [29]. Moreover, Kuang et al. showed that in the peritumoral stroma of HCC, there is a fraction of monocytes/macrophages which express PD-L1 and mediate the inhibition of the anti-tumoral T cell response [30]. Furthermore, cancer cells can produce factors such as granulocyte-macrophage colony stimulation factor (GM-CSF), VEGF, and poly-unsaturated fatty acids that can attract myeloid-derived suppressor cells (MDSCs). This phenotype of myeloid cells consists of the presence of immature neutrophils and monocytes mobilized from the bone marrow with an increased ability to produce ROS, RNS, prostaglandin E2 (PGE2), and anti-inflammatory cytokines, both systemically and in the TME. These characteristics confer the ability to suppress adaptive immunity and can facilitate tumor progression and metastasis [31]. MDSCs can then be pathologically activated in situ by different pro-inflammatory cytokines and DAMPs, such as interferon (IFN)γ [32], IL-1β [33], IL-6 [34], tumor necrosis factor (TNF)α [35], and HMGB1 [36]. Hypoxia plays an important role in the maintenance of MDSCs through the HIF-1α-mediated expression of ectonucleoside triphosphate diphosphohydrolase 2 in cancer cells [37]. In general, hypoxia has been associated with the shift toward an immunosuppressive TME [38]. In HCC, an increased number of MDSCs correlates with disease progression and reduced overall survival [39]. Many works have also linked liver inflammation, HCC initiation, and progression to the deregulation of complement system activity. The physiological functions of the complement system can enable the recovery from acute liver injury; however, the excessive and long-lasting activation of the complement cascade induces hyperproliferation and tumorigenesis, activating, for example, NF-kB or STAT3 in the KCs and hepatocytes [40]. Notably, unrestrained complement activation has been linked with tumor progression in other cancer settings [41]. In the following paragraphs, we aim to discuss the physiological regulatory nature of the liver immune milieu and the mechanisms through which tolerance can be interrupted, paving the way for HCC. 

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