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Page 2 of 14 Monge Bonilla et al. Hepatoma Res 2020;6:68 I http://dx.doi.org/10.20517/2394-5079.2020.58

HCC can be caused by both viral and non-viral factors. HCC develops secondary to chronic infection
with the hepatitis B virus (HBV) or hepatitis C virus (HCV). High serum levels of HBV DNA and HCV
RNA viral load are considered to be independent risk factors for developing HCC in patients infected by
[8]
[6,7]
these diseases . HBV vaccination has greatly reduced the incidence of HCC in certain geographic areas .
Moreover, improved screening and treatment of HCV infection has also reduced virus-related HCC cases
in non-epidemic regions .
[9]
Non-viral risk factors for the development of HCC include excessive alcohol consumption, environmental
[10]
exposure to aflatoxin, metabolic disorders, non-alcoholic steatohepatitis, and genetic disorders . It
is unsurprising that non-viral risk factors are more common causes of HCC in countries such as the
USA, UK, and other high income countries. Frequently, viral infection is complicated with non-viral
risk factors leading to HCC development. Systematic treatment is the standard approach to control
advanced HCC, given that most patients present with advanced stage disease, which limits curative
approaches such as surgical resection, liver transplantation, and local liver-directed therapy. Recent
molecular landscape analysis has led to the development of systematic targeted therapies for advanced
[11]
[12]
HCC, including sorafenib and lenvatinib in the first line setting, and regorafenib , cabozantinib ,
[14]
[13]
[15]
and ramucirumab as second line options. The breakthrough of cancer immunology research has
provided effective immunotherapy by blocking immunosuppressive mechanisms and enhancing host
immune surveillance. This leads to the recognition of tumour and execution of a tumour-specific response
capable of treating malignancy, including HCC . HBV- or HCV-related HCC represents a special entity
[16]
compared to non-viral HCC. This review discusses the immune response to HBV and HCV infection, the
immunology of HCC, and summarizes the current status of immunotherapy in HCC in the context of HBV
or HCV infection.
HBV INFECTION AND IMMUNE TOLERANCE
Studies have shown that HBV not only has a direct carcinogenic effect through the integration of viral
DNA and the oncoprotein HBV-encoded X protein (HBx), but also has an indirect carcinogenic effect due
[17]
to chronic immune suppression . HBV has been considered as a stealth virus and acute infection does
not lead to a strong activation of interferon (IFN) and pro-inflammatory responses [18-22] . Liver resident
macrophage Kupffer cells are able to interact with hepatitis B surface antigen (HBsAg) and produce pro-
inflammatory cytokines, but Toll-like receptor expression is down-regulated by HBeAg [23,24] . Indirect
activation of natural killer (NK) cells can occur via Kupffer cell derived IL-12 and IL-18 [23,25] , evidenced by
the increased expression of activation markers CD69 and NKG2D and lower levels of inhibitory markers
[28]
NKG2A [26,27] , but these are functionally suppressed . These suggest that NK cells are unable to clear the
infection on their own. The weakness of the innate response does not impair the induction of a vigorous
[29]
HBV-specific CD4 T cell response , that subsequently generates a large number of cytokines necessary
[30]
for the effective development of cytotoxic CD8 T cells and B cell antibody production . Potent HBV
+
antigen-specific CD8 T cell responses can control HBV replication and reduce it to undetectable levels
[31]
during acute HBV infection . In chronic HBV infection, the antiviral functionality of NK cells is also
[32]
impaired, evidenced by an alteration of the phenotype and the receptors of NK cells . This inhibition
of NK cell activity is mainly mediated by myeloid-derived suppressor cells (MDSCs) via NKp30 receptor
[34]
[33]
on NK cells and pro-inflammatory cytokines . In addition, accumulated liver MDSCs due to HBV
[35]
infection suppress CD8+ T cell function and promote systemic CD8+ T cell exhaustion , characterized
by high expression levels of inhibitory receptors such as CTLA-4, PD-1, and TIM-3 [36,37] . Furthermore,
they inhibit CD4+ T cells and metabolically regulate HBV-related liver damage . MDSCs can induce the
[38]
development of immunosuppressive regulatory T cells (Tregs) during chronic HBV infection primarily
[39]
via a TGFb and the IL‐10-dependent signalling pathway . Tregs specifically inhibit CD8+ T cell activity;
further blocking HBV-specific immune responses, leading to HBV persistence. On the other hand, low
+
levels of HBV activity controlled by HBV antigen-specific CD8 T cells lead to sustained liver inflammation