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Page 12 of 18 Qin et al. Hepatoma Res 2020;6:24 I http://dx.doi.org/10.20517/2394-5079.2020.04

the immunotherapy group was clearly longer than control group (44 months vs. 30 months). Cancer-related
death was also lower in the CIK group than in the no immunotherapy group (P = 0.02); 17% of patients
experienced adverse reactions related to CIK cytokines, but there was no difference in severe adverse
events [140] .

In addition, the efficacy and safety of the combination of CIK cells with liver-directed therapies in HCC were
also evaluated. In a study that evaluated CIK cells combined with TACE + RFA in HCC patients. overall
efficacy in the TACE + RFA + CIK group was better than in the TACE + RFA group (76.5% vs. 79.8%).
Kaplan-Meier analysis indicated that the overall survival rate of the TACE + RFA + CIK treatment group was
significantly prolonged (56 months vs. 31 months, P = 0.001) [141] . In another study, HCC patients with Child-
Pugh scores of A or B and without prior treatment were enrolled. One group (n = 66) received CIK treatment
and standard treatment, while another group (n = 66) received standard treatment only. The results showed
that overall survival and PFS were significantly prolonged after treatment with CIK cells in patients who
were not suitable for surgery [142] . Furthermore, one study found that targeting MDSCs is a good strategy to
enhance the antitumor efficacy of CIKs for the treatment of patients with HCC [143] .

Although more and more studies have shown that CIK cells makes up a significant part of HCC treatment,
only a portion of T cells can provide a full antitumor function because of immune escape mechanisms and
lack of specific tumor antigens.

TILs
TILs are isolated from tumor tissue and induced by IL-2 in vitro. TILs are relatively rare in HCC, but they
play an important role in tumor recurrence in patients. A phase I clinical trial indicated that immunotherapy
with autologous TILs could be successfully performed with low toxicity [144] . In another randomized clinical
trial, 76 HCC patients were enrolled and the ratio of postoperative recurrence was significantly lower in the
group using IL-2 to activate lymphocytes compared to the control group [145] . Furthermore, the functions of
tumor-infiltrating T cells were restored via the antibodies targeting immune checkpoints [146] . Until now, the
widespread use of TIL immunotherapy has been limited, mainly because of difficulties in purification and
amplification.

NK cells
NK cells belong to innate immune cells, and the main feature is that they can directly destroy tumor cells
without prior stimulation. Preclinical experiments showed that CXCR6 can inhibit hepatocarcinogenesis
+
by promoting natural killer T cell- and CD4 T cell-dependent control of senescence [147] . Another study
also confirmed that expanded activated NK cells are highly cytotoxic to HCC cells. The function of NK
cells against HCC were enhanced by the expression of NKG2D-CD3ζ-DAP10 [148] . Tan et al. [149] reported
that LrNK cells were observed to be present in liver cancer, often showing abnormal function. Moreover,
this dysfunction is caused by Tim-3-mediated PI3K/mTORC1 interference. However, there is still a lack of
clinical trials of NK cells in the treatment of HCC, so more clinical studies are urgently needed.

SUMMARY AND FUTURE EXPECTATIONS OF IMMUNOTHERAPY IN HCC
With the development of molecular biotechnology and tumor immunology, immunotherapy has been an
important part in the mode of combined therapy of tumors. Along with the gradually deepened study of
molecular biology and molecular immunology, T cells have an important influence on tumor immunity in
the hepatic microenvironment. Recently, there have been a large number of studies on HCC immunotherapy,
and some of them have achieved important positive results. At present, many preclinical studies demonstrate
that vaccine therapy, adoptive cell therapy and immune checkpoint inhibitors make up a significant part
in inhibiting the growth and development of HCC. Moreover, more clinical trials of immunotherapy for
liver cancer are being conducted. In early clinical trials, tremelimumab, nivolumab, pembrolizumab and