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Qin et al. Hepatoma Res 2020;6:24 I http://dx.doi.org/10.20517/2394-5079.2020.04 Page 5 of 18

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[46]
the in vitro response of CD8 T cells by affecting IL-10 and IDO . Furthermore, CD4 helper T cells are
substantially important in generating functional memory CD8 T cells by inducing costimulatory molecules
and promoting the expression of extracellular cytokines in DCs [47,48] .

DCs
NK cells are another participant in innate immunity, capable of initiating T cells against TAAs that are
[49]
specialized APCs involved in HCC progression .

In HCC, DCs can produce chemotactic cytokines, and take the initial T cells as the point of action to
[50]
promote their aggregation and proliferation . Moreover, DCs can promote the maturation of B lymphocytes,
[51]
enhance the immune response mediated by antitumor antibodies, and suppress immune escape . The
available evidence suggests that DC maturation disorder, function decrease and reduction in peripheral
blood are often observed in the HCC microenvironment, often leading to tumor development [52,53] .

In HCC, DC function is inhibited due to the production of some factors (IL-10, IL-6, etc.) in the tumor
[55]
[54]
microenvironment . Beckebaum et al. confirmed that IL-10 has a considerable immunosuppressive
effect on circulating DCs in HCC patients. In addition, previous studies have shown that DCs can promote
[46]
immunosuppression by producing IL-10 and IDO in HCC, but that depends on the expression of CTLA4 .
In general, in recent years, DCs have been widely used as new vaccines in the treatment of solid tumors such
as liver cancer, prostate cancer, kidney cancer, melanoma, etc. [56,57] .

MDSCs
Myeloid-derived suppressor cells MDSCs comprise a mixture of macrophages, monocytes, granulocytes
[58]
and DCs, which are a heterogeneous population of immature myeloid cells . Some previous investigations
revealed that MDSCs participate in immunosuppressive networks and are potential immunotherapy targets
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[63]
for HCC [59-62] . A study by Zhou et al. showed that immunosuppressed CD11b CD33 HLA-DR MDSCs
were stimulated and amplified by hepatic CCRK by increasing IL-6 expression in human peripheral blood
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mononuclear cells. In addition, they also found that tumor-infiltrating CD11b CD33 HLA-DR MDSCs
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potently inhibited autologous CD8 T cell proliferation in HCC patients. MDSCs express galectin-9 and bind
[64]
to TIM-3 on T cells to induce T cell apoptosis .
In HCC patients, MDSC can also impair function of NK cells by inhibiting their cytotoxicity and cytokine
[66]
[65]
release . Furthermore, Hu et al. showed that MDSCs can inhibit the production of IL-12 induced by
TLR-ligand via the expression of IL-10 and can inhibit T lymphocyte activity. In summary, MDSCs play a
variety of immunosuppressive roles in HCC.
Given that MDSCs play a variety of immunosuppressive roles in HCC, the immunotherapy targeted MDSC
has become a research hotspot. Some previous research has shown that the combination of radiotherapy
and IL-12 (RT/IL-12) may reduce accumulation of tumor-infiltrating MDSCs and reverse the intratumoral
[67]
immunotolerant state and improve the immune level in HCC . In addition, targeting MDSCs and
combining anti-PD-1/PD-L1 can synergistically enhance the cure of HCC [63,68] .

Hepatic stellate cells, endothelial cells and kupffer cells
In addition to that described above, hepatic stellate cells (HSC) are an important element in the
microenvironment of liver tumor. Previous research has shown that HSC can secret hepatocyte growth
[69]
factor/cytokines, which lead to decreased antitumor immunity function . In addition, hepatocyte growth
factor (HGF) secreted by activated HSC promotes the invasiveness and tumorigenicity of HCC [70,71] .

Compared with normal tissues, the endothelial cells of HCC are significantly different in molecular and
functional aspects. Endothelial cells are involved in tumor neovasculature and play a significant role in