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Page 2 of 12 Zhang et al. Hepatoma Res 2020;6:40 I http://dx.doi.org/10.20517/2394-5079.2020.20

Cancer immunotherapy was selected as its annual breakthrough in Science journal in 2013. Following the
advancements of immunotherapy in solid tumors over the last few years, as shown by the results of immune
[8]
checkpoint inhibitors (ICIs) in lung cancer, renal cell cancer and melanoma , in recent years, ICIs with anti-
[9]
CTLA-4 antibodies and anti-PD-1/PD-1L antibodies have been utilized to treat advanced melanoma . In
2018, because of the achievements in the treatment of cancer with ICIs of CTLA-4 and PD-1/PD-L1, James P.
Allison and Tasuku Honjo were awarded the Nobel prize.

Chimeric antigen receptor T‐cell (CAR-T) immunotherapy has become more popular in the last decade
as an antitumor therapy. Anti-CD19 CAR-T cell was approved by the FDA for treatment of subjects up to
[10]
25 years of age with B-cell acute lymphoblastic leukemia in 2017 . This article mainly summarizes the
advances in ICIs and cellular immunotherapy for HCC.

PD-1/PD-L1
PD-1 is expressed on a subset of thymocytes and is upregulated on activated T cell, B cell, and myeloid
[11]
cells . Two ligands for PD-1 were identified in 2000 and 2001 and named PD-L1 and programmed death
ligand 2 (PD-L2), respectively [12,13] . PD-L1 is mainly expressed on stationary T cells, B cells, DC, and
hepatoma cells, while PD-L2 is only expressed on DC and macrophages [14-16] . In theory, the interaction of
PD-1 and PD-L1 expressed on immature T cells can interfere with activation. Similarly, if PD-L1 is highly
expressed on tumor cell, the ligand receptor interactions between tumor cells and activated T cells triggers
[17]
the immunosuppressive response, leading to immune tolerance . It provides a theoretical basis for the
treatment of PD-L1 in HCC.

It has been demonstrated that PD-L1 is overexpressed in HCC tissues; however, the results are controversial
[18]
with respect to PD-L1 as predictive biomarkers for HCC . Several studies have reported that the higher
PD-L1 expression on tumor cell in HCC patients were related with worse prognosis and tumor recurrence,
and the studies also showed PD-L1 expression on macrophages was associated with favorable survival
rate [19-23] . However, two studies suggested that the expression of PD-L1 was not significantly correlated with
survival outcomes in HCC [24,25] . Both soluble PD-1 (sPD-1) and soluble PD-L1 (sPD-L1) were prognostic
factors with opposite prognostic values for HCC patients, while sPD-1 and sPD-L1 were not significantly
[26]
related with PD-L1 expression in tumor . However, two studies suggested plasma sPD-1 was associated
with HBV activity and increased risk of HCC [27,28] .

[29]
Liang et al. illustrated that inhibition of PD-1 can suppress the growth of hepatoma and promote the
apoptosis of hepatoma. Increased expression levels of PD-1 were detected in peripheral blood and tumor
[30]
infiltrating lymphocytes (TILs) of recurrent HCC patients . Blockade of PD-1 on TILs can restore anti-
[31]
tumor effects of TILs . However, sPD-1/sPD-L1 was not associated with either PD-L1 expression of
[26]
tumor cell or the numbers of CD4-positive TILs and CD8-positive TILs . Tumor infiltrating neutrophils
as a new target of immunotherapy participate in tumor progression, while the tumor microenvironment
(TME) induces impaired antitumor immunity via the modulation of PD-L1 expression on tumor infiltrating
[23]
[32]
neutrophils . PD-L1 was positively associated with expression of CD3 and CD8 in HCC samples . PD-L1
expression on macrophages is also a prognostic factor for HCC patients, and it could activate high levels of
[21]
CD8(+) cytotoxic T-lymphocyte (CTL) infiltration and immune related gene expression .
Since immune checkpoint molecules are recognized as vital indicators of HCC progress, series of clinical
trials with ICIs have been implemented to confirm their potential function for advanced HCC. Nivolumab
[33]
was approved by the FDA as immunotherapy for advanced stage HCC in 2017 . The efficiency of nivolumab
was observed in a Phase I/II non-comparative trial (CheckMate 040) of patients with HCC and prior
[33]
sorafenib treatment . Forty-eight patients were treated with nivolumab in a dose-escalation phase. Then,
since nivolumab showed adequate safety and feasibility, 214 patients from 39 sites in 11 countries received