Page 64 - Read Online

Page 4 of 12 Ni et al. Hepatoma Res 2020;6:25 I http://dx.doi.org/10.20517/2394-5079.2020.14

the TME. In addition, these modulators can also induce previously silent neoantigens and elicit neoantigen-
[18]
specific T cell responses to control tumors .

Combination therapy with yttrium-90 radioembolization and PD-1 ICB for HCC treatment was also
[19]
studied . 26 consecutive HCC patients who received PD-1 ICB and radioembolization from April
2015 to May 2018 were included in a single-center, retrospective study. The results indicate that PD-1
ICB combined with yttrium-90 radioembolization in cases of HCC appears to be well-tolerated. Future
prospective studies are needed to optimize treatment protocols and evaluate the efficacy of combination
[19]
therapy .

ADVANCEMENT OF DENDRITIC CELL-BASED HCC VACCINES
The response of HCC to ICB has been disappointing and new strategies are being explored. Tumor-
associated antigen-loaded DCs are a potential immunotherapy for cancer, since DCs are the strongest
professional antigen-presenting cells, which can orchestrate the innate and adaptive immune systems.
Sipuleucel-T, the first FDA-approved DC vaccine, was observed to be effective in the treatment of human
[20]
prostate cancer to some extent . In the context of HCC, DC-based immunotherapy has recently been
reported. Although HCC in China develops from chronic hepatitis B virus (HBV) infection, most HCC
cells containing HBV-DNA fragments do not encode entire HBV antigens, but HBV epitopes can be
encoded. To date, several tumor-associated antigens have been identified for DC-based vaccines for the
treatment of patients with HCC including alpha-fetoprotein, glypican-3, melanoma associated antigen-1
and aspartate β-hydroxylase.

Alpha-fetoprotein (AFP) is a glycoprotein derived from embryonic endoderm tissue. Expression levels of
AFP in fetal serum are high and decrease over time. While mature hepatocytes lose the ability to synthesize
AFP, liver cancer cells can synthesize AFP after transformation. Hence, AFP has been detected in several
malignant tumors, including that of the stomach, pancreas and liver. The majority of human HCC cells
[21]
express high levels of AFP in Eastern populations . Therefore, HCC patients with negative or weakly
positive AFP in serum are associated with highly differentiated cancers. Glypican-3 (GPC3), another
tumor-associated antigen, is a heparan sulfate proteoglycan, which binds to glycosylphosphatidylinositol-
anchored proteins and can be detected in the liver and kidneys of healthy fetuses. Adults express low or
no GPC3, except in the placenta. GPC3 is also specifically expressed in several types of cancers including
HCC, ovarian clear cell carcinoma, melanoma, squamous cell carcinoma of the lung, hepatoblastoma,
nephroblastoma (Wilms tumor), yolk sac tumors, and some pediatric cancers. In some trials, HLA-A24-
and A2-restricted GPC3-derived peptide vaccines elicited GPC3-specific cytotoxic T cells in most
[22]
vaccinated patients and in turn, improved outcomes . Melanoma antigen 1 family contains a lot of
chromosome X-clustered genes, including MAGE-1, MAGE-B and MAGE-C groups. Most of them
[23]
cannot be detected in normal adult tissues except in the testis . However, various types of cancers highly
express it, including HCC. MAGE-1 protein-derived peptides are currently being studied as targets for the
[24]
development of cancer vaccines . Aspartate β-hydroxylase (ASPH), a type II transmembrane protein, is
a highly conserved dioxygenase enzyme, which is overexpressed in a variety of cancers, including HCC.
Normal adult tissues rarely express ASPH, except in placental trophoblastic cells. In HCC patients, ASPH
overexpression was significantly correlated with higher relapse and lower survival rates after surgery, and
could also predict worse surgical outcomes in early-stage HCC patients . The expression pattern of ASPH
[25]
makes it a potential biomarker and therapeutic target in cancer.

[26]
[27]
In phase I/IIA and phase II trials, Lee et al. [26,27] showed that autologous DC vaccines prepared by
loading with the three most common HCC TAAs (AFP, MAGE-1, and GPC-3) in order to cover HCC
heterogeneity were safe and well tolerated in HCC patients. In addition, DC vaccination led to enhanced
tumor-specific immune responses. Therefore, adjuvant immunotherapy with DC vaccines decreases the