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Monge Bonilla et al. Hepatoma Res 2020;6:68 I http://dx.doi.org/10.20517/2394-5079.2020.58 Page 3 of 14

Figure 1. Schematic mechanism of immune evasion across the spectrum from inflammation by chronic hepatitis B (HBV) and C virus
(HCV) infection to resultant hepatocellular carcinoma (HCC). The complexity of the mechanism involves multiple immune cells and
various collections of cytokines. A: immune tolerance induced by HBV and HCV infection; B: immune evasion driven by the crosstalk
between tumour cells and immune cells in HCC. DC: dendritic cells; MDSCs: myeloid-derived suppressor cells; TAMs: tumour-
associated macrophages; NK: natural killer; NKT: natural killer T; Treg: regulatory T-cells; CAF: cancer-associated fibroblast; HBV:
hepatitis B virus; HCV: hepatitis C virus; MHC: major histocompatibility complex; TCR: T-cell receptor; IL: interleukin; IFNg: interferon
gamma; TNFa: tumour necrosis factor receptor alpha; TGF-β: transforming growth factor beta; CCL: C-C motif chemokine ligand;
CXCL: C-X-C motif ligand 1; Gal-9: galactin-9; PD-1: programmed cell death protein; PD-L1: programmed cell death ligand 1; CTLA:
cytotoxic T-lymphocyte-associated protein; IL: interleukin; Arg-1: arginase-1; Tim-3: T cell immunoglobulin and mucin domain 3; LAG-3:
lymphocyte-activation gene 3; SDF-1: Stromal cell-derived factor 1

+
and the functional depletion of HBV antigen-specific CD8 T cells [40-42] . Hence, immunotherapies targeting
+
these inhibitory receptors may modulate the progression of HCC [Figure 1]. Moreover, the exhausted CD8
T cells experience impaired metabolic function and DNA repair capacity that further deteriorates their
[43]
functions . This highlights a complex interaction among the abovementioned immune cells during HBV
infection, sustaining immune disorders and inflammation in the liver, which predispose patients to HCC
development.

HCV INFECTION AND IMMUNE TOLERANCE
The dysregulation in immune surveillance triggered by HCV infection is also thought to be one of the
mechanisms by which HCV causes HCC. During acute HCV infections, NK cells are activated with
enhanced cytotoxicity and IFN production . However, 70% of HCV-infected patients progress to chronic
[44]
[45]
[46]
infection , partially due to decreased NK cell levels and function . HCV antigen-specific CD8+ T
[47]
cells participate in controlling HCV infection . However, non-synonymous mutations in HCV are
common, resulting in an escape from CD8+ T-cell recognition [48,49] . Moreover, HCV antigen-specific T cells
undergo massive apoptosis during the chronic phase . It has been reported that CD8+ T cell exhaustion
[50]
develops following prolonged exposure to HCV antigens [51-53] . During chronic infection, HCV activates
monocytes and macrophages, leading to the secretion of pro-inflammatory cytokines . The released pro-
[54]
[55]
inflammatory cytokines IL-6 and TNF not only promote macrophage apoptosis , but also aggravate liver
[56]
disease progression and HCC development . In the setting of HCV infection, impaired macrophage
phagocytosis may contribute to chronic infection and subsequent uncontrolled inflammation that promotes
[57]
liver disease. Similar to HBV, HCV infection is also linked to the presence of MDSCs and an expansion
[58]
of Tregs via IL-10 and IL-12 [59,60] . Tregs both suppress the HCV antigen-specific CD8+ T cell response
in chronic infection and control memory cells. In addition, HCV impedes dendritic cell (DC) function by
+
+
altering the adaptive response of CD4 and CD8 T cells, and cytokine release [61,62] . This suggests that HCV
often disturbs antigen presentation along with humoral and cell-mediated immune response, resulting in
chronic HCV infection and progressive liver damage [Figure 1].