Page 68 - Read Online

Page 8 of 12 Ni et al. Hepatoma Res 2020;6:25 I http://dx.doi.org/10.20517/2394-5079.2020.14

subgroup with high hepatitis B viral load. PD-L1 expression however, did not correlate with patient survival
[46]
in the surgery alone group . These findings suggest that PD-L1 expression can serve as a biomarker for
predicting survival benefit from adjuvant CIK cell immunotherapy in HCC patients.

T cell receptor gene-engineered T cells
Genetic engineering of TAA-specific T cell receptor (TCR) could be an option to yield AFP-specific
CTLs. AFP is overexpressed in HCC and serves both as a TAA as well as a potential target for adoptive
immunotherapy. However, the low percentage and exhausted AFP-specific T cells in vivo impedes adoptive
immunotherapy. Genetic modification with TCRs that are specific for HCC-associated antigens, such
as AFP, strongly redirect human T cells to specifically eliminate HCC tumor cells. Using lentivector and
+
[47]
peptide immunization, Zhu et al. identified a population of CD8 T cells in HLA-A2 transgenic AAD
mice that recognized the AFP158 epitope on human HCC cells. Adoptive injection of the AFP158-specific
+
mouse CD8 T cells killed HepG2 tumor xenografts in immunocompromised NSG mice. T cell hybridoma
clones from the AFP158-specific mouse CD8 T cells were then established and three sets of paired TCR
+
genes were identified out of five hybridomas. The murine TCR-expressing primary human T cells can
bind to HLA-A2/AFP158 tetramer. TCR gene-engineered T (TCR-T) cells also specifically recognized and
+
+
eliminated HLA-A2 AFP HepG2 HCC tumor cells, but had no toxic effect on normal primary hepatocytes
in vitro. Notably, AFP-specific TCR-T cells could kill HepG2 tumors in NSG mice. These findings suggest
that AFP158-specific TCRs have the ability to engineer HLA-A2-positive autologous T cells to treat
patients with HCC . Sun et al. used AFP158-166 peptide-loaded autologous DCs to stimulate AFP-
[47]
[48]
specific CTLs. TCR genes of AFP-specific CTLs were then cloned into a lentiviral vector, which in turn
infected nonspecific activated T cells. The specific cytotoxic activity against HpeG2 in vitro and in tumor-
bearing NOD/SCID mice was significantly enhanced in engineered CTLs than that in AFP-specific CTLs
stimulated by peptide-loaded DCs or controls. TCR gene transfer is thus a promising strategy to yield AFP-
[48]
specific CTLs for HCC .
In China, around 85% of HCC is associated with HBV infection. Cells from most HBV-associated HCCs
contain HBV-DNA fragments that fail to encode entire HBV antigens, but do encode epitopes of HBV-
specific T cells. Given that, autologous TCR-T cells that recognize epitopes from HBV-DNA in patients’
metastases were infused into two patients without notable toxicity. This strategy might be exploited for
[50]
[49]
a wider population of patients with HBV-related HCC . Qasim et al. , also showed HBV antigen
expression in HCC metastases. T cells were then genetically engineered to express an HBsAg specific
TCR to treat chemo-resistant extrahepatic metastases. Genetically-engineered T cells reduced HBsAg
levels without exacerbation of liver inflammation or other adverse effects. This study further supports this
[50]
approach in treating patients with HBV-associated HCC .
Gamma-delta T cells
Gamma-delta (gd) T cells have been found to be promising as cellular immunotherapy in HCC patients .
[51]
The amplifying ability of circulating gd T cells was related with the clinicopathological characteristics of
patients, such as clinical stage, levels of AFP and albumin, duration of disease, size and number of tumors,
numbers of Tregs and gd T17 cells, and levels of IL-17A. Notably, the frequency of gd T cells that were
positive for IFN-g, TNF-a, granzyme B, perforin, and lysosome-associated membrane protein remained
unchanged both before and after amplification. More importantly, the in vitro cytotoxicity of gd T cells
remained unchanged, which may render them feasible for HCC immunotherapy. However, adoptive
[51]
transfer of gd T cells should be individualized based on the clinicopathological features of patients .
Natural killer cells
Natural killer (NK) cells play a pivotal role in eradicating virus-infected and transformed cells in the
[52]
innate immune system. Kamiya et al. successfully expanded NK cells from peripheral blood of healthy
donors by using the K562-mb15-41BBL cell line as a stimulus. Following expansion, NK cells showed great