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Page 6 of 12 Zhang et al. Hepatoma Res 2020;6:40 I http://dx.doi.org/10.20517/2394-5079.2020.20

DCs pulsed with Hsp70 peptide and OK-432 can enhance efficacy of vaccine inducing T cell proliferation
and CTL response [91,92] . In a clinical trial using Hsp70-DC vaccination, 2/12 patients demonstrated complete
[93]
response and 5/12 patients demonstrated stable disease . In our previous meta-analysis, we concluded DC-
[94]
based therapy could prolong the median progression free survival (PFS) time and median OS time .
However, the maturation of DC was closely associated with efficacy of DC immunotherapy. The stimulatory
capacity of dendritic cells from HCC patients was significantly lower than dendritic cells from liver cirrhosis
[95]
tissue and normal samples . Meanwhile, the numbers of CD83-positive DCs in HCC specimens were
[96]
significantly lower compared with liver cirrhosis samples . Therefore, it is very important to improve the
maturation of DC, increase antigen source, and depress TME. Various stimuli, such as tumor necrosis factor
alpha, lipopolysaccharide, IFN gamma, CD40-ligand, PEG10, IL-12, EpCAM, and HCA661, can significantly
increase the stimulatory capacity of DCs [97-102] . Tumor endothelial marker 8 modified DCs could stimulate
antitumor immunity by disrupting tumor vasculature, and DCs loaded with specific peptide, such as FoxM1,
could significantly inhibit tumor growth and metastasis [103,104] . In addition, RFA can create an antigenic
source with stimuli appropriate for maturation of DCs [105] . Regulatory T cells, producing immunosuppressive
cytokine IL-10, were concentrated within HCC tissue and were inducted by local TME to interfere the
[7]
differentiation and maturation of DC . To overcome the immunosuppressive TME, Hu et al. [106] introduced
a promising vaccine candidate, which combine the DC/tumor cell fusion vaccine with nanoparticles of
folate-modified chitosan carrying interferon-induced protein-10, which could effectively inhibit tumor cell
proliferation and significantly reduce myeloid-derived suppressor cells in mouse immune organs.

CIK/DC-CIK
CIK are a subset of non-MHC-restricted T lymphocytes with immune modulatory effects and a crucial
role in anti-tumor immunotherapy [107] . Several studies suggested that CIK cells co-cultured with DCs can
significantly enhance antitumor efficiency [108,109] . Qiu et al. [110] reported that alpha-Gal epitope-pulsed DC-
CIK therapy remarkably prolonged the survival of patients with stage III primary HCC as compared to the
controls (17.1 months vs. 10.1 months). In a retrospective study from 45 patients with metastatic HCC,
median OS of DC-CIK immunotherapy plus ablation (32 months) or ablation (17.5 months) was higher than
untreated group (3 months) [111] . In a propensity score-matched analysis, autologous CIK immunotherapy
showed significantly longer RFS than the control group [112] . After 5-year follow-up, CIK immunotherapy
show a significant reduction in the risk of recurrence or death [113] . The combination therapies DC-CIK with
other therapeutic options, such as TACE, could improve the antitumor efficacy. Guo et al. [114] reported that
DC-CIK therapy combined with TACE can improve the PFS but not the OS outcomes. However, TACE plus
DC-CIK therapy for HCC patients is superior to TACE alone in improving median OS and PFS in a meta-
analysis [115] . Zhou et al. [116] analyzed that clinical benefit rate of sorafenib combined with DC-CIK is higher
than oral administration of sorafenib (88.6% vs. 41.9%) in a meta-analysis.

To enhance the therapeutic efficacy of CIK cells, several pre-clinical studies suggested that co-culture of
modified DCs, such as IL24-modified DCs, AFP-modified DCs, and GPC3-modified DCs, with CIKs can
significantly promote CIKs differentiation and enhance lytic activity of CIK cells [117-119] . They provided a
promising DC-CIK vaccine candidate for further clinical trials of HCC patients. Indeed, CIK or DC-CIK
immunotherapies from autologous or allogeneic donors have already been extensively used in solid tumor
patients. In our clinical center, we have experience with more than 100 gastric cancer patients with DC-CIK
immunotherapy and have found that treatment outcomes were effective, safe, and feasible for gastric cancer
patients. The standardization in the preparation and criteria of indication are progressing; several clinical
trials are registered and ongoing. CIK or DC-CIK immunotherapies, combined with other antitumor agents,
should be considered.