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Page 2 of 12 He et al. Hepatoma Res 2018;4:40 I http://dx.doi.org/10.20517/2394-5079.2018.45

common, malignant liver cancer. The overall prognosis for HCC patients is poor, with a dismal 5-year
survival rate of approximately 5%-30% .
[1,2]

The most common progression of liver cancer is from chronic inflammation to cirrhosis and eventually
developing to HCC through a prolonged period leading to multiple function disorders. Immunosuppression
may be one of the most important reasons. T cell dysfunction, also known as T cell exhaustion, occurs
in chronic infections and cancers. Various cell populations, including infiltrating immune cells and
tumor cells, stroma cells with related cytokines and metabolites, cause T cell dysfunction in the tumor
microenvironments. Exhausted T cells lack robust effector functions and express multiple inhibitor receptors
that reduce efficient immunological surveillance of tumor . Tumor recurrence and relapse-free survival
[3,4]
(RFS) are correlated to CD3+, CD8+ immune cells or tumor infiltrating lymphocytes (TILs), as well as
the inhibitory receptors such as programmed cell death protein 1 (PD-1) and its ligand . The potential
[5]
immunosuppressive mechanism involves the hepatoma-intrinsic cell cycle-related kinase (CCRK) signaling
stimulated by the expansion of the polymorphonuclear (PMN) myeloid-derived suppressor cells (MDSCs),
which have been correlated to potent T cell suppression and poor prognosis of patients . Expression of
[6,7]
ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2) on the surface of cancer cells is induced by
hypoxia, which elevates extracellular 5’-AMP and prevents the differentiation of MDSCs, consequently,
contributing to the maintenance of MDSCs .
[8]

Recently, cancer immunotherapy has emerged from being an adjacent to a frontline therapy and has
demonstrated positive outcomes involving various cancers. Antagonistic antibodies for the PD-1 and cytotoxic
T cell lymphocyte antigen-4 (CTLA-4) pathways have been approved by the Food and Drug Administration
(FDA) for use in a growing number of cancers, including Hodgkin’s lymphoma (HL), melanoma, bladder,
non-small-cell lung and kidney cancers [9,10] . Tumor tissue deep sequencing has advanced the neoantigen-
based vaccines [11,12] and neoantigen-specific T cells [13-16] to clinical trials and resulted in discovering significant
antitumor effects that will make individualized immunotherapy become a reality. In 2017, 2 kinds of chimeric
antigen receptor (CAR) T cells that target CD19 have received FDA approval for treatment of diffuse large
B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL), respectively [17-19] . Here, we provide an
overview of current preclinical and clinical immunotherapeutic approaches for HCC.

IMMUNOTHERAPY APPROACHES
Cancer vaccine
Promoting tumor specific immune responses, especially the cytotoxic CD8+ T cells is the main goal of
cancer vaccines. In colorectal cancer (CRC), breast cancer and ovarian cancer, the reduced frequency of
tumoral cytotoxic CD8+ T cells is correlated with poor disease prognosis [20-23] . On the other hand, it is a
positive prognostic factor in that TILs are present in tumor deposits. The investigation of vaccines that
target specific mutated antigens is being encouraged due to the technological developments in the recent few
years. Several kinds of cancer vaccines are being tested, for instance proteins, peptides, tumor cells, antigen
presenting cells (APC), and viral vectors.

Vaccination with antigens
The first step toward DC vaccine production is loading tumor antigens on the immature dendritic cells (DCs).
Tumor antigen candidates could be mutated genes, neoantigens, viral genes, tissue-specific genes, whole
proteins, deoxycholate citrate sugar (DCA) constructs and tumor lysates of autologous or allogeneic tumor
cells or tumor cell lines, which belong to either tumor-associated antigens (TAAs) or tumor-specific antigens.

Alpha-fetoprotein (AFP) is a fetal serum protein produced in the liver and is normally synthesized only
during fetal development until shortly after birth, while it is produced again in instances of HCC. Specific