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Page 2 of 18 Lee et al. Hepatoma Res 2018;4:51 I http://dx.doi.org/10.20517/2394-5079.2018.78

INTRODUCTION
Hepatocellular carcinoma (HCC) ranks fifth as the most common cancer in the world and the second most
[1-3]
common cause of cancer-related death, accounting for 70%-85% of primary liver cancers . The current
standard treatments for HCC offer a fair chance of survival but there are still many patients who struggle
[4]
with only a limited chance of survival . A majority of patients present with disease too advanced to be treated
with curative modalities such as surgical resection, transplantation, or radiofrequency ablation (RFA) .
[2]
Although the Barcelona Clinic Liver Cancer (BCLC) guideline recommends sorafenib in advanced HCC,
which proved a survival benefit of 2.8 months compared to the placebo group , many liver cancer centers
[5]
still select multimodality approaches including transarterial chemoembolization (TACE), radiotherapy
(RT), and hepatic arterial infusion chemotherapy (HAIC) .
[6,7]
Most HCCs arise on a background of chronically inflamed liver, and thus are considered typical immunogenic
[8]
cancers . Based on the immunological mechanisms thought to be acting during HCC development, the
effects of diverse immunomodulatory regimens such as therapeutic vaccination, immune checkpoint
[8,9]
inhibitors, and transfer of adoptive cellular immunotherapy, have been investigated . In the 21st century,
cell-based therapies developed to bolster human anti-tumor immunity represent a growing component of
cancer therapeutics [10,11] . Of note, adoptive cellular immunotherapies have employed several types of immune
cells, including dendritic cells (DCs), cytotoxic T lymphocytes (CTLs), lymphokine-activated killer (LAK)
cells, cytokine-induced killer (CIK) cells, and natural killer (NK) cells . In addition, therapeutic cancer
[12]
vaccines utilizing tumor antigens with or without DCs have been investigated.

Immune suppressor cells comprising tumor-associated macrophages (TAMs), regulatory T cells (Tregs),
or myeloid-derived suppressive cells (MDSCs) in the HCC tumor microenvironment, could disturb the
immune surveillance resulting in cancer immune evasion or immune escape . It is well known that the
[13]
interactions of HCC cells with the immune cells and their factors of immune system play a major role
in its progression [14,15] . Inadequate co-stimulation, failure of tumor-associated antigens (TAAs) processing
and presentation by antigen-presenting cells (APCs), along with suppression of effector cells are proposed
mechanisms that result in weakened immune response in HCC patients [15,16] . To complement these
immunosuppressive tumor microenvironment of HCC, previous cancer immunotherapy has aimed so far
to enhance immune cell activity to kill the HCC tumor cells.

In this regard, cancer vaccines help the immune system recognize and attack cancer cells . Unlike preventive
[17]
vaccine, which prevents a development of a certain disease in advance, therapeutic cancer vaccine aims to
treat the existing cancer. DCs are professional APCs that serve as a key player for inducing and activating the
effector anti-tumor CTLs. There is ample evidence to justify therapeutic DC vaccines in HCC . Decreased
[18]
function of peripheral blood DCs in patients with HCC is well established . Up to date, although DC
[19]
vaccines are used in various stages of clinical trials of HCC, unfortunately, no therapeutic cancer vaccine has
been approved for HCC . Meanwhile, the failure of these approaches for boosting immune responses by
[19]
cancer vaccine using peptides or DCs, could be associated with the brake function in immunity (i.e., immune
checkpoints) . It is now clear that tumors modulate immune checkpoints as one of the mechanisms to
[20]
escape anti-cancer immune surveillance.

These immune checkpoints are known to regulate different stages and signaling processes of the immune
response . At the initial stage of “priming” of naïve T cell activation, cytotoxic T lymphocyte associated
[21]
antigen-4 (CTLA-4):B7 binding blocks stimulatory signals, and stops the development of potentially
autoreactive T cells . Compared to CTLA-4, the major role of programmed cell death 1 protein (PD-1)
[22]
and its ligand, PD-L1, is related to regulate previously activated CTLs at the later “effector” stage of immune
response . In the tumor microenvironment, antigen-specific T cells induce PD-1 expression on reactive
[23]
CTLs and upregulate PD-L1 in cancer cells [8,23] .