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Li et al. Hepatoma Res 2020;6:15 I http://dx.doi.org/10.20517/2394-5079.2019.34 Page 5 of 13

[81]
HCC . These findings indicate that CLTA-4 is a promising target for HCC treatment. Recently, the
CTLA-4 blockade agent, ipilimumab, has been tested in clinical trials of HCC treatment, with a partial
[83]
[82]
response rate of 18% and a disease control rate of 76% . Duffy et al.’s study demonstrated that
tremelimumab could achieve a partial response rate of 26% and a disease control rate of 84%. Furthermore,
the combination therapy of ipilimumab and nivolumab could achieve objective response rates of 31% and
[84]
a median duration of 17.48 months in advanced HCC patients . As with other cancers, the combination
regimens of nivolumab and ipilimumab led to grade 3-4 treatment-related adverse events occurring in
37.7% patients, which were more frequently observed with combination regimens than with single-agents,
especially in patients who received higher dosages of ipilimumab. However, most of the adverse events were
manageable with timely recognition, steroid treatment, and discontinuation of immunotherapy, with a very
low rate of liver failure [73,85,86] .

Other immune checkpoint inhibitors
The binding of inhibitory killer-immunoglobulin-like receptors (KIRs) expressed on NK cells with HLA
[87]
class I molecules inhibit the activation of NK cells . Antibodies against inhibitory KIRs enhance NK
cell cytotoxicity. It was reported that KIR/HLA immunogenetic background influenced the evolution of
HCC [88,89] . Anti-KIR antibodies - IPH2101 and IPH2102 - were well tolerated in patients with relapsed
multiple myeloma [90,91] . However, little evidence emerged to confirm the efficacy of these anti-KIR antibodies
+
against HCC. NKG2A is an inhibitor receptor expressed on both CD8 T cells and NK cells [92,93] . Therefore,
+
anti-NKG2A mAb promoted anticancer immunity of both CD8 T and NK cells [94,95] . It has been shown that
[22]
NKG2A mediated NK-cell exhaustion in patients with HCC . However, the effect of anti-NKG2A mAb on
HCC needs to be confirmed in clinical trials. Increasing inhibitory receptors such as IL-1R8, TIM3, TIGIT,
and CD96 have been found to be important for regulating NK cell activity against tumors [96-100] . Clinical trials
have been performed to evaluate the efficiency of antibodies against these checkpoints for cancer therapy.
The efficacy of NK cell-based checkpoint inhibitors in HCC needs further preclinical and clinical studies.

Combination therapy with immune checkpoint inhibitors
Immune checkpoint blockade leads to recovery of immune response against HCC cells and suppression
of tumor growth in HCC. However, most HCC patients still do not achieve clinical benefit from ICI
immunotherapy, highlighting the need for creative strategies to improve therapeutic efficacy. First, novel
checkpoints need to be identified in HCC. For example, B and T cell lymphocyte attenuator has been
found to participate in suppressing CD4 T cell function in HCC [101] . Siglec-15 has been confirmed to be
+
an immune suppressor and displays promising efficacy in cancer immunotherapy [102] . The roles of novel
checkpoints in HCC have not been addressed. Second, novel combinations of checkpoints need to be
[42]
designed. Zhou et al. found that T cells isolated from HCC tissue expressed high levels of PD-1, CTLA4,
TIM3, and LAG3, suggesting the involvement of multiple checkpoints in T-cell exhaustion in HCC. The
[42]
efficacy achieved by combining blockade of checkpoints was better than that by single checkpoint alone .
Therefore, a combination of ICIs might achieve better results than just monotherapy for HCC treatment.
Moreover, the individualized combination for HCC patients can be designed based on omics-data to achieve
precision medicine. Third, novel comprehensive combination needs to be tested. Wehrenberg-Klee et al. [103]
reported that combining radioembolization with nivolumab could enhance the ICI-induced anticancer
immune response. Shigeta et al. [104] found that dual anti-PD-1/VEGFR-2 therapy enhanced CD8 cytotoxic
+
T cell anticancer immune response in HCC. PD-1/PD-L1 double blockade increased anticancer immune
response of vaccine-induced CD8 T cells in advanced HCC patients [105] . To improve the benefits of ICI, it
+
is necessary to integrate ICI therapy with targeted agents, locoregional therapy, vaccines, or other forms of
therapy. Of note, the clinical outcomes of such integration require further investigation in future studies.

Adoptive cell transfer
+
NK cells and CD8 T cells eliminate cancer cells by direct cytotoxicity. In advanced HCC, the scarcity of
NK cells and CD8 T cells in HCC tissues eliminates the ICI-induced anticancer efficacy. In this setting, it is
+
absolutely necessary to adaptively transfer cytotoxic immune cells into patients with advanced HCC.