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Lominadze, Z.; Hill, K.; Shaik, M.R.; Canakis, J.P.; Bourmaf, M.; Adams-Mardi, C.; Abutaleb, A.; Mishra, L.; Shetty, K. Immune-Focused Pathophysiology of Hepatocellular Carcinoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/41226 (accessed on 13 April 2024).
Lominadze Z, Hill K, Shaik MR, Canakis JP, Bourmaf M, Adams-Mardi C, et al. Immune-Focused Pathophysiology of Hepatocellular Carcinoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/41226. Accessed April 13, 2024.
Lominadze, Zurabi, Kareen Hill, Mohammed Rifat Shaik, Justin P. Canakis, Mohammad Bourmaf, Cyrus Adams-Mardi, Ameer Abutaleb, Lopa Mishra, Kirti Shetty. "Immune-Focused Pathophysiology of Hepatocellular Carcinoma" Encyclopedia, https://encyclopedia.pub/entry/41226 (accessed April 13, 2024).
Lominadze, Z., Hill, K., Shaik, M.R., Canakis, J.P., Bourmaf, M., Adams-Mardi, C., Abutaleb, A., Mishra, L., & Shetty, K. (2023, February 14). Immune-Focused Pathophysiology of Hepatocellular Carcinoma. In Encyclopedia. https://encyclopedia.pub/entry/41226
Lominadze, Zurabi, et al. "Immune-Focused Pathophysiology of Hepatocellular Carcinoma." Encyclopedia. Web. 14 February, 2023.
Immune-Focused Pathophysiology of Hepatocellular Carcinoma
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The emerging field of immuno-oncology has brought exciting developments in the treatment of hepatocellular carcinoma (HCC). It has also raised urgent questions about the role of immunotherapy in the setting of liver transplantation, both before and after transplant. A growing body of evidence points to the safety and efficacy of immunotherapeutic agents as potential adjuncts for successful down-staging of advanced HCCs to allow successful transplant in carefully selected patients. For patients with recurrent HCC post-transplant, immunotherapy has a limited, yet growing role.

hepatocellular carcinoma immunotherapy liver transplantation

1. Introduction

Globally, hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer-related deaths [1]. In the United States, it is the 6th leading and the most rapidly rising cause of cancer deaths [2][3]. Worldwide, the most common etiologies of liver disease predisposing to HCC are chronic viral hepatitis B and C, alcohol-related liver disease, and non-alcoholic or metabolic liver disease [4]. The American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and the Asian Pacific Association for the Study of the Liver (APASL) all recommend screening for HCC with abdominal ultrasound (with or without alpha fetoprotein (AFP)) in appropriately selected patients: those with cirrhosis of any etiology, and in certain sub-groups with chronic hepatitis B [5][6][7]. However, the sensitivity of AFP as a screening test for detecting HCC is only about 41–65% (based on a systematic review of patients with chronic hepatitis C) [8], and the sensitivity of ultrasound for detecting early-stage HCC is approximately 63% [9]. In addition to the limitations in sensitivity of existing screening tests, adherence to the screening guidelines themselves is sub-optimal: a systematic review and meta-analysis of studies from around the world found a 24% pooled proportion of patients undergoing surveillance [10].
Given these challenges in detecting early-stage HCC, it is no surprise that the prognosis of HCC varies widely. Patients with resectable lesions have a 5-year survival of approximately 70% following surgical intervention [6][11][12], whereas the median overall survival of untreated terminal-stage HCC (Barcelona Clinic Liver Cancer stage D) is only 1.6–6 months [2]. Patients between these two extremes comprise a heterogeneous group, with multiple possible treatment pathways. These include thermal ablation techniques (microwave and radiofrequency), bland embolization, trans-arterial chemoembolization (TACE), trans-arterial radioembolization (TARE), external beam radiation therapy (EBRT) modalities including proton beam therapy, liver transplantation (LT), and systemic treatments. For patients who qualify for LT, whether upon initial diagnosis based on the Milan criteria, or after “down-staging” with local-regional therapies, 5-year survival is excellent at 70–80% [4][13][14].
The emerging field of immunotherapy has brought exciting developments in the treatment of numerous cancers and has the potential to revolutionize the approach to intermediate and advanced-stage HCC. The landmark Checkmate 040 trial led to the Food and Drug Administration (FDA) approval for the use of the immune checkpoint inhibitors (ICIs) nivolumab (directed against programmed death-1, or PD-1) plus ipilimumab (directed against cytotoxic T-lymphocyte-associated-protein 4, or CTLA-4) for the treatment of advanced HCC previously treated with sorafenib [15]. Shortly thereafter, the IMbrave150 clinical trial led to the FDA approval of atezolizumab (a programmed death-ligand 1, or PD-L1 inhibitor) plus bevacizumab (a monoclonal antibody targeted at vascular endothelial growth factor, or VEGF) as first line therapy for advanced stage HCC [16]. Recently presented phase 3 data (HIMALAYA trial) with the novel immunotherapeutic combination of durvalumab (another PD-L1 inhibitor) plus tremelimumab (another anti-CTLA-4 antibody) demonstrated better overall and progression-free survival compared to sorafenib as first line treatment [17][18]. The FDA approved this combination on 21 October 2022, making it an attractive first-line option in advanced HCC.
The current choice of therapy for HCC is dictated by hepatic synthetic function, presence or absence of portal hypertension, patient performance status, and tumor burden. The American Society of Clinical Oncology guidelines recommend atezolizumab-bevacizumab or the tyrosine kinase inhibitors (TKIs) sorafenib or lenvatinib as first-line therapy [19]. The choice of second-line therapy is dependent on initial treatment. For patients who progress on TKIs, second-line therapy options include another TKI (such as cabozantinib or regorafenib), immunotherapy (atezolizumab-bevacizumab, pembrolizumab, or nivolumab), or ramucirumab (a VEGF receptor inhibitor) for those with AFP levels greater than 400 ng/mL. Those treated with durvalumab-tremelimumab or atezolizumab-bevacizumab as first-line therapy may be offered TKIs such as sorafenib, lenvatinib, regorafenib or cabozantinib [19].
Multiple studies have established the benefit of immunotherapeutic agents in the treatment of HCC, and many studies are ongoing [20][21]. Preliminary studies of chimeric antigen receptor (CAR) T cells have also shown promise in treating advanced or recurrent HCC [22][23]. Finally, combining immune-oncology (IO) and interventional radiology (IR) treatments in a complementary fashion has led to the proposition for a more formalized “IR-IO” approach in treating early and intermediate stage HCC [24].

2. Immune-Focused Pathophysiology of HCC

HCC usually occurs in the setting of advanced chronic liver disease, such as advanced hepatic fibrosis or cirrhosis, or chronic hepatitis B with necro-inflammatory activity. In these settings, a plethora of inflammatory and immune mediated responses contribute to the development and survival of HCC.
Kupffer cells, which form part of the reticuloendothelial system of the liver, are the resident macrophages found in hepatic sinusoids. Pattern recognition receptors found on these cells are stimulated by pathogen-associated molecular patterns (PAMPs) leading to the expression of pro-inflammatory cytokines such as IL-6, as well as immunomodulatory molecules including IL-10 and TGF-β [25]. Mouse studies have shown liver sinusoidal endothelial cells expressing low levels of major histocompatibility complex (MHC) class II molecules CD80 and CD86. Vital for helper T cell differentiation, the lack of these molecules provides a mechanism of immune escape for HCC [25][26].
Another mechanism of immune evasion by cancer cells is through the upregulation of T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs). CD4+CD25+ Tregs account for 5–10% of the CD4+ T cell population in the human body. These cells are known to suppress both CD4+ and CD8+ T cells through various means including secretion of TGF-β, IL-10, and IL-35 [27][28][29]. CTLA-4, expressed and activated on Tregs, has a higher affinity for CD80 and CD86 which acts as a competitive inhibitor to CD28, a T cell activator. Through this binding, CTLA-4 can activate indoleamine-2,3-dioxygenase (IDO) and subsequently suppress T cell mediated cytotoxic immune responses [30]. A meta-analysis from 2014 including twenty-three studies showed patients with HCC had 87% more circulating Tregs compared to healthy controls [29].
Similarly, MDSCs have been shown to suppress CD4+ and CD8+ T cells, inhibit natural killer cell cytotoxicity, and prompt the development of Tregs [31]. Accumulation of MDSCs in the liver leads to interaction with Kupffer cells, inducing PD-L1 expression on their surface. PD-L1 interacts with PD-1 and leads to suppression of IFN-γ [31]. MDSCs along with tumor associated macrophages (TAMs) also play an important role in angiogenesis: secretion of VEGF, platelet-derived growth factor (PDGF), and matrix metalloproteinase-9 (MMP-9) by TAMs and MDSCs leads to increased tumor vasculature, providing nutrients for tumor growth [32][33]. In turn, increased expression of PD-1 on T cells has been associated with incomplete response to HCC local-regional therapy and impaired survival, possibly mediated by the phenomenon of T cell exhaustion [34].
Through secretion by Tregs and MDSCs, anti-inflammatory cytokines promote tumor growth and are associated with a worse prognosis [35]. Some of the cytokines studied in HCC include the previously mentioned IL-10 and TGF-β. While IL-10 has been shown to be increased in patients with HCC compared to those with only cirrhosis or healthy controls, it is also elevated in those with chronic viral hepatitis [36]. Therefore, this immune-suppressive cytokine may be useful as an HCC tumor marker, though with limited utility in those with chronic viral hepatitis. Meanwhile, TGF-β, initially thought to be tumor suppressive, functions as a tumor promoter in later stages of HCC. Produced by tumor cells, macrophages, or Tregs, it downregulates the antitumor response by various mechanisms: it inhibits the activation of dendritic cells, promotes M2 polarization of TAMs, impairs the effector functions of T cells and NK cells, and promotes the generation of induced Treg cells [37]. One recent mouse study demonstrated that FGFR4 contributes to tumor proliferation and invasion through activation by TGF-β1 in the extracellular signal-related kinase (ERK) pathway; silencing FGFR4 expression was found to inhibit this activity [38]. Higher levels of TGF-β1 have been shown to be correlated with higher tumor grade, shorter survival, and overall poor prognosis [39][40]. In addition, higher TGF-β1 and TGF-β levels, respectively, have been associated with poor response to the TKI sorafenib and ICI pembrolizumab [41][42].
Several signaling pathways have also been studied in the development and progression of HCC. These include the Ras/Raf/MAPK, PI3/AKT/mTOR, JAK/STAT, and the Ubiquitin-Proteasome pathway. Transcription factors including c-myc and c-jun, among others, are associated with these pathways and are involved in 30–60% of HCCs [43]. Of these, one of the most crucial is the Wnt/β-Catenin pathway, with 20–40% of HCC cases harboring mutations within this complex [43]. Specifically, mutations in CTNNB1 which encodes β-catenin, as well as AXIN1 and APC (antigen presenting cell) encoding other important components, have been shown to occur in up to a combined 35% of human HCC samples [44]. Furthermore, activation of this pathway is shown to mediate resistance to ICI treatment for HCC, with upregulation of this signaling pathway correlating to lower overall survival rates and resistance to anti-PD1 therapies [45][46].

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