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Guerra, P.; Martini, A.; Pontisso, P.; Angeli, P. Immune Classification of Hepatocellular Carcinoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/47406 (accessed on 01 August 2024).
Guerra P, Martini A, Pontisso P, Angeli P. Immune Classification of Hepatocellular Carcinoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/47406. Accessed August 01, 2024.
Guerra, Pietro, Andrea Martini, Patrizia Pontisso, Paolo Angeli. "Immune Classification of Hepatocellular Carcinoma" Encyclopedia, https://encyclopedia.pub/entry/47406 (accessed August 01, 2024).
Guerra, P., Martini, A., Pontisso, P., & Angeli, P. (2023, July 29). Immune Classification of Hepatocellular Carcinoma. In Encyclopedia. https://encyclopedia.pub/entry/47406
Guerra, Pietro, et al. "Immune Classification of Hepatocellular Carcinoma." Encyclopedia. Web. 29 July, 2023.
Immune Classification of Hepatocellular Carcinoma
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This entry is adapted from the peer-reviewed paper 10.3390/cancers15143629

Hepatocellular carcinoma (HCC) is a common and aggressive cancer with a high mortality rate. The incidence of HCC is increasing worldwide, and the lack of effective screening programs often results in delayed diagnosis, making it a challenging disease to manage. Immunotherapy has emerged as a promising treatment option for different kinds of cancers, with the potential to stimulate the immune system to target cancer cells. However, the current immunotherapeutic approaches for HCC have shown limited efficacy. Since HCC arises within a complex tumour microenvironment (TME) characterized by the presence of various immune and stromal cell types, the understanding of this interaction is crucial for the identification of effective therapy.

hepatocellular carcinoma immunotherapy immune system inflamed class tumour microenvironment

1. Introduction

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, followed by Cholangiocarcinoma (CCA). It is the fourth cause of cancer death worldwide and there has been an increase of 75% in its incidence in the last years [1][2]. The overall 5-year survival is 18%, making it the second most lethal tumour after pancreatic cancer [3].
HCC arises in 90% of the cases in the setting of chronic liver disease (CLD), and cirrhosis of any aetiology is its strongest risk factor [4]. There is evidence that suggests that it can also develop during the progression of Non-Alcoholic Fatty Liver Disease (NAFLD) even before the stage of cirrhosis [5][6][7].
Curative treatments, such as surgical resection or radiofrequency ablation, can be applied in the early stages [8]. Surveillance programs rely on the dosage of serum alpha-fetoprotein and the execution of abdominal ultrasound to detect early-stage tumours [9][10][11]. Nevertheless, it has been estimated that the diagnosis is incidental in 50% of cases globally [4], precluding most of the patients to undergo curative treatment. This is why there is a huge need for novel biomarkers or strategies to improve surveillance.
According to the Barcelona Clinic Liver Cancer (BCLC), the treatment algorithm suggested by the European Association for the Study of the Liver (EASL), indicates that tumours in the advanced stage must be treated with systemic therapy [12]. Accordingly, other Guidelines indicated systemic therapy as the first choice for treatment of advanced stages [13][14][15].
Since some years ago, the standard of systemic treatment was based on tyrosine kinase inhibitors (Sorafenib, Lenvatinib, Cabozantinib or Regorafenib). In addition, new drugs and natural compounds have been proposed, such as sanguinarine, targeting HIF-1α and TGF-β signalling pathways, which leads to subsequent EMT and cell migration inhibition [16]. Several studies have revealed indeed that sanguinarine impedes tumour metastasis, however, its low chemical stability and poor oral bioavailability remain key issues that are currently approached using novel release methods and developing alternative analogues [17].
Over the past decade, immuno-oncology has taken the lead in the treatment of malignancies including liver cancer and consequently, several new drugs have been approved, including anti-VEGF and Immune Checkpoint Inhibitors (ICI) [18].
Despite the initial success of the new therapies, evidence suggests that there are different problems to overcome: the response rate of ICI monotherapy is 20%, while combination therapy reaches approximately 30–36% [19][20][21]. One of the mechanisms of resistance to ICI therapy can be the low expression or absence of immune checkpoints [22]. In other kinds of solid tumours, including breast, lung and oesophageal cancer, screening for the presence of PD-L1 is an effective way to predict the response to the therapy [23][24][25]. Unfortunately, due to the complexity of HCC pathogenesis and microenvironment, this approach did not achieve the same results for hepatocellular carcinoma.
Still, clinical trials, which have demonstrated the efficacy of immunotherapeutic agents, have found interesting differences and provided possible hypotheses to overcome this problem.
In the IMbrave150 phase III clinical trial Atezolizumab, an anti-programmed death ligand 1 (PD-L1) monoclonal antibody, in association with Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, has been shown superior to Sorafenib [26]. More recently, according to the results of the HIMALAYA trial, the association of Tremelimumab, an anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody, and Durvalumab (anti-PD-L1 monoclonal antibody) have been added to the possible first-line strategy of systemic therapy [27].
Subgroup analysis of clinical trials has uncovered an important difference in the response to ICI therapy depending on the aetiology of CLD and HCC [28]. In the IMbrave150, patients with non-viral aetiology did not show benefits of Atezolizumab and Bevacizumab over Sorafenib treatment (HR for death, 1.05; 95% CI, 0.68–1.63) [29]. On the other hand, in the HIMALAYA trial, the superiority of Tremelimumab and Durvalumab was confirmed for HBV-infected and non-viral patients, but not for HCV-infected patients (HR, 1.06; 95% CI, 0.76–1.49) [30].
Moreover, in the KEYNOTE-240 trial, comparing Pembrolizumab (anti-PD-L1 monoclonal antibody,) vs. placebo in patients pre-treated with Sorafenib, the overall survival (OS) was significantly higher in patients with HBV infection than in non-viral or HCV-related CLD [31]. However, in the CheckMate 450 trial, comparing Nivolumab, an anti-programmed death 1 (PD1) monoclonal antibody to Sorafenib as first-line treatment, HBV and HCV-infected patients showed a better response than non-viral patients, although the difference was not statistically significant [32]. Finally, the LEAP-002 trial, comparing Pembrolizumab vs. Lenvatinib did not show any difference according to aetiology [33].
These conflicting results should be taken with caution since they originate from post hoc analysis and the number of patients included was quite small. However, it is important to consider that when analysing the response to therapy, the aetiology of CLD and HCC is an important factor.
On this line, several hypotheses have been provided. For example, in preclinical models of Non-Alcoholic Steatohepatitis (NASH) related HCC an accumulation of exhausted CD8+PD-1+ cells has been reported [34]. Although treatment with anti-PD-1 led to an increase in CD8+ infiltration, tumour regression was not achieved. This finding is likely since NASH-related CLD causes aberrant T-cell activation and impaired immune surveillance.
A second proposed mechanism of resistance to immunotherapy is the presence of strong inhibition of the immune response by the Tumour Microenvironment (TME) [21].
Given the important role of the immune system in HCC development and response to therapy, the following classification of HCC, based on tumour immune characteristics has been recently proposed.

2. The Inflamed Class: Immune-Active, Immune-Exhausted and Immune-like

Sia et al. [35] reported for the first-time evidence that in a group of 228 patients, up to 25% had an increase in markers of the inflammatory response, increased cytolytic activity and enhanced PD1 and PDL1 expression. They termed this group the immune class and later defined the inflamed class.
The inflamed class was then divided into two subclasses: the immune-active and the immune-exhausted. The first one is characterized by the presence of Interferon (INF) signature, T cells and adaptive immune response gene expression, while the second one is dominated by TGF-beta signalling and other immunosuppressive components. Interestingly, the two classes do not differ in the immune infiltration, Tertiary Lymphoid Structures (TLS) number, PD-L1 and PD-1 expression. The immune-active class demonstrated to have lower recurrence after resection, and better survival and was found as an independent prognostic factor of overall survival, suggesting that the state of activation of the immune system plays an important role in defining the TME role and tumour behaviour.
Since the inflamed class included only 25% of the HCCs analysed in the first study, new subclasses were identified in the following study [36]. A group of tumours with characteristics similar to those of the inflamed class was identified and classified as an “immune-like class”. This subgroup, presenting clinical and pathological characteristics similar to those of the immune classes, was characterized by high INF signalling, immune infiltration, M1 macrophage differentiation and remarkable activation of Wnt-beta-catenin signalling.

3. The Non-Inflamed Class: Immune-Intermediate and Immune-Excluded

The non-inflamed class was identified by Montironi and colleagues [36] and comprises the remaining 63% of liver tumours that do not fulfil the criteria to enter into the inflamed class. It can be divided into immune-intermediate and immune-excluded, based on the mechanism of immune evasion.
The immune-intermediate class is characterized by a decrease in immune infiltration associated with TP53 mutations and higher levels of deletions in genes related to INF signalling and antigen presentation.
The immune-excluded class is characterized by the lowest level of immune infiltration, associated with a high frequency of CNNTB1 mutation, causing an activation of the Wnt-beta-catenin pathway that can inhibit leukocyte migration, thus causing a profound suppression of the immune response, as described previously.
This classification could be clinically useful for different reasons. First of all, the inflamed class was characterized by the presence of two inflammatory signatures predicting ICI response, although additional studies are needed to prove this correlation. Secondly, the possibility of identifying each class signature using liquid biopsy might be useful in a clinical setting to avoid invasive procedures.

References

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Subjects: Gastroenterology & Hepatology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Pietro Guerra
,
Andrea Martini
,
Patrizia Pontisso
,
Paolo Angeli
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Update Date: 31 Jul 2023
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