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Page 4 of 13 Li et al. Hepatoma Res 2020;6:15 I http://dx.doi.org/10.20517/2394-5079.2019.34

[57]
HCC tissues by restraining PD-1 degradation . The complicated immunosuppressive microenvironment
+
in HCC tissues severely impairs the efficacy of immunotherapy. Therefore, the mechanisms of CD8 T-cell
exhaustion in HCC needs to be further elucidated.

CYTOTOXIC IMMUNE CELL-BASED IMMUNOTHERAPY OF HCC
+
The increased understanding of CD8 T cells and NK cells promotes the development of effective
immunotherapy. These two immune cell populations follow many similar patterns and/or complementary
patterns to eliminate cancer cells. Moreover, their activities are regulated by common immune checkpoints.
Here, we discuss the application and outcomes of cytotoxic cell-based ICIs and ACT in HCC treatment.

Immune checkpoint inhibitors
ICIs have displayed impressive efficacy in treating a variety of cancers. An increasing number of studies
are being conducted on novel immune checkpoints and their inhibitors. Additionally, studies on ICI-
based immunotherapy for advanced HCC treatment are also increasing, with some showing encouraging
therapeutic effects.

Anti-PD-1 antibody and anti-PDL1 antibodies
+
+
PD-1 is mainly expressed on CD8 T cells, whose binding with PD-L1/PD-L2 induces CD8 T-cell
[58]
high
exhaustion . T cells from HCC tissues express high levels of PD-1 [59,60] . Interestingly, PD-1 B cells in HCC

+
+
[61]
tissues suppressed CD8 T-cell anticancer immunity by secreting IL-10 . Moreover, PD-1 dendritic cells
[62]
+
(DCs) in HCC tissues also suppressed CD8 T-cell anticancer immunity . In addition, PD-1 ligands are
[65]
associated with aggressiveness and recurrence of HCC [63,64] . Wu et al. reported that PD-L1 on Kupffer cell
+
blocks CD8 T-cell anti-HCC activity. Besides, hepatoma cell-expressed PD-L1 induces apoptosis of CD8
+
[66]
T cells and promotes HCC recurrence . Additionally, PD-L1-expressing monocytes induce polarization
[67]
of Th22 cells through PD-1 in HCC tissues . PD-L1 on intratumoral hepatic stellate cells or peritumoral
neutrophils also contributes to the impairment of T cell-mediated anti-HCC immunity [68,69] . These
findings indicate that blockade of PD-1/PD-L might be promising immunotherapy for HCC. Nivolumab
and pembrolizumab gained approval for treatment of advanced HCC based on encouraging results from
phase I/II studies in advanced HCC patients with objective response rates of 17%-20% [70,71] . However,
results from two phase III clinical studies did not reveal statistically significant improvement in survival
benefit [72,73] . There are several ongoing trials with monoclonal antibodies against PD-1, such as nivolumab,
pembrolizumab, tislelizumab, and camrelizumab, in HCC patients, either as monotherapy or in combination
with other treatments. A phase-I/II study reported that the combination of atezolizumab and bevacizumab
[74]
resulted in a 62% response rate in advanced HCC patients . The breakthrough therapy of atezolizumab
in combination with bevacizumab is recently approved as a first-line treatment for patients with advanced
or metastatic HCC. Moreover, a randomized phase III study demonstrated superior overall survival and
[75]
progression-free survival compared to sorafenib in the first-line treatment of advanced HCC . In addition,
another antiangiogenic drug ramucirumab has been approved as a second-line therapy for advanced HCC
[76]
following first-line therapy with sorafenib . The clinical efficacy from the combination of anti-PD-L1 with
antiangiogenic agents encourages researchers to extensively develop novel combination strategies to improve
the clinical efficacy of HCC treatment.
Anti-CTLA-4 antibody
CTLA-4 is expressed on Treg cells and activated T cells and inhibits T-cell activation by competing for
[78]
[77]
CD80/CD86 with CD28 . Liu et al. found that CTLA-4 polymorphism may have negative effects on
[50]
+
HCC. CTLA-4 Treg cells impair T cell-mediated anti-HCC immunity . HCC-derived Treg cells limit
[79]
+
DCs function by CTLA-4 . Furthermore, CTLA-4 DCs suppress T cell-mediated anti-HCC immunity by
[80]
IL-10 and IDO . Fortunately, CTLA-4 blockade with glucocorticoid-induced tumor necrosis factor receptor
family-related protein (GITR) engagement completely abrogates Treg-mediated immunosuppression in