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Page 8 of 15 Song et al. Hepatoma Res 2020;6:27 I http://dx.doi.org/10.20517/2394-5079.2020.05

clearance [121] . Furthermore, combined OX40 stimulation and PD-L1 blockade effectively activate IFN-γ
producing Th1 cells and IL-21 producing Tfh cells, which potentiates the application of immunotherapeutic
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approaches [122] . Consistent with anti-tumor function in HBV-related HCC, surveillance from CD4 T
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cells are crucial for NAFLD [123,124] . However, selective loss of CD4 T cells has been recently detected in
NAFLD, which promotes hepatocarcinogenesis [125] . Mechanistically, linoleic acid (C18:2) is released from
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dead hepatocytes caused by lipotoxicity into CD4 T cells. C18:2 then co-localizes within mitochondria,
upregulating expression of carnitine palmitoyltransferase, which further promotes production of ROS and
cell apoptosis [124] .

B cells
HBV viral load as well as HBsAg and HBeAg levels differed with progression of distinct phases of chronic
HBV infection, accompanied by alteration of immune cells. Immunoglobulin-encoding genes and B cell
function-related genes are more enriched in immune active patients than those in immune tolerant and
inactive carrier patients [126] . B-cell response and humoral immunity are essential for controlling progression
of chronic HBV infection [127,128] . However, differentiated HBsAg-specific B cells from patients with CHB are
defective in antibody production and express high levels of inhibitory receptors, such as PD-1, FcRL4 and
FcRL5 [112,129] . Blockade of PD-1 on B cells effectively reverses cellular dysfunction to maturation and cytokines
secretion [111] . Mechanistically, HBsAg inhibit toll-like receptor (TLR) promoter activity by suppressing
phosphorylation of CAMP responsive element binding protein (CREB), thereby comprehensively inhibits
expression of TLR9 in B cells, leading to reduced proliferation of B cells and decreased proinflammatory
cytokines secretion [130] .

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Intrahepatic B cells are highly associated with NAFLD. CD20 B cells are increased in liver tissues from
NAFLD patients with activity score higher than 5, compared with those of 0 or 1~4 [131] . Consistently, hepatic
B cells account for more in HFD-induced NAFLD mice than in control mice. Moreover, the B cells in
NAFLD liver tissues potentiate to produce higher levels of IL-6 and TNF-α, and promote differentiation
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of CD4 T cells to Th1 cells [132] . Functionally, the maturation of hepatic B2-cells and the increase of IgG
in circulation targeting oxidative stress-derived epitopes predict the onset of steatohepatitis, and B cells-
mediated activation of Th1 cells contributes to NAFLD progression toward fibrosis [133] .

IMMUNOTHERAPIES
As discussed above, a long duration is taken for both HBV- and NAFLD-related HCC, therefore, treatments
aiming at eliminating HBV infection or blocking NASH progression and fibrogenesis can prevent the
development of tumors. Abundant alterations of hepatic immune cells during liver carcinogenesis provide
wide-range targets. Several immunotherapies have been approved for clinical application, nonetheless, the
induced resistance and adverse events remain to be further investigated. The following sections will discuss
immunotherapies in HCC, such as immune checkpoint inhibitors, virus or tumor vaccines, and adoptive
cells transfer.

Immune checkpoint blockade
Inhibitory checkpoint receptors (ICRs) including CTLA-4, PD-1 and PD-L1, are recognized as master
regulators for anti-tumor immunity. Immune checkpoint inhibition (ICI) therapy using antibody against
PD-1, PD-L1 and CTLA-4 have been since been approved by the Food and Drug Administration [134] .
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Moreover, function of exhausted CD8 T cells is restored through implementation of anti-PD-1 therapy
and even combined blockade of ICRs [113,114] . In a cohort study with 262 patients enrolled between 2012 and
2016, nivolumab, a monoclonal antibody against PD-1, showed a decent safety profile, including acceptable
tolerability [135] . Consistently, safety and efficacy of nivolumab was comparable in Asian patients, compared
to intent-to-treat overall population [136] . However, a phase III trial showed that pembrolizumab, another
PD-1 inhibitor, did not display significant increase in overall survival (OS) and progression-free survival