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Page 4 of 18 Qin et al. Hepatoma Res 2020;6:24 I http://dx.doi.org/10.20517/2394-5079.2020.04

TANs are one of the key factors for HCC progression and poor prognosis, and neutrophil-lymphocyte ratio
closely correlates with tumor progression, which is a significant independent factor predicting survival
after hepatectomy in patients with liver cancer [23,24] . In peripheral blood, the highest levels of the cytokines
CCL17 and CCL2 are produced by peripheral blood neutrophils activated by HCC cells and TANs. The
newest discovery shows that TANs mediate the intratumoral infiltration of TAMs and regulatory T cells
[25]
by overproducing CCL2 and CCL17, which then contributes to HCC progression and metastasis .
[25]
Zhou et al. collected and analyzed HCC patients’ clinical and pathological data, and the results showed that
+
the number of CCL2 or CCL17 TANs was related to tumor progression and differentiation. Moreover, these
+
authors also found that TANs triggered the secretion of microRNA 301b-3p by releasing bone morphogenic
protein 2 and transforming growth factor beta 2 (TGFβ2) in HCC cells, and then increased the expression of
HCC stem cell-like cells by inhibiting the expression of the limbic system-associated membrane protein and
CYLD lysine 63 deubiquitinase genes. From this research, a positive feedback loop governing cancer stem-
[26]
like cells and TANs in HCC were identified . TANs play a significant role in immunosuppression in HCC,
unfortunately, the exact underlying mechanisms between TANs and other molecules in HCC are not quite
clear.

Innate lymphocytes
The liver is a non-lymphoid organ although possessing anti-tumor capabilities, due to containing large
populations of natural lymphocytes including NK cells, NKT cells, etc. [27-29] . The activation of NK cells rely
[30]
on a cascade of multiple activated and inactivated receptors . In the oxygen-deficient liver environment, the
function of NK cells will be impaired due to hypoxia-inducible factor 1α (HIF-1α), which induces changes
[31]
in MHC class I polypeptide-related sequence A (MICA) . HIF-1α is important for regulates metabolism,
cell proliferation and apoptosis of in HCC microenvironment [31,32] . In the presence of HIF-1α, proangiogenic
genes including vascular endothelial growth factor (VEGF) gene are frequently overexpressed in immune
[33]
cells .
It is reported that α-fetoprotein (AFP) can directly influence the functions of NK cells. Short exposure of
NK cells to AFP can promote the IL-2 hyperresponsive phenotype and contribute to the release of IL-6,
IL-1β and TNF-α, which is related to a low recurrence rate and better overall survival of HCC patients with
[36]
HBV [34,35] . Moreover, NK cell functions can be impaired via TGF-ß1, IL-8 and IL-10 released by Tregs .

Tregs
+
Tregs belong to the subset of CD4 T cells, which do not merely suppress autoimmune response, but
[39]
also impair the immune response against tumors [37,38] . Gao et al. demonstrated that Tregs represent an
independent predictor of HCC recurrence and survival, and is related to invasiveness and intratumoral
homeostasis. They also found that the combination of Treg removal and simultaneous stimulation of
effector T cells was an effective immunotherapy to decrease recurrence and prolong postoperative survival.
+
CD4 CD25 Tregs were used to contribute to tumor prevention in HCC patients through various contact-
+
+
[40]
+
+
dependent and contact-free mechanisms. Fu et al. further demonstrated that CD4 , CD25 and FoxP3
+
Tregs impaired the function of CD8 T cells effector and that the number of circulating Tregs correlated with
progression in HCC patients. In addition, another study showed that that compared with normal tissues,
[41]
where CD4 CD25 T cells were significantly increased in the area around the tumor .
+
+
CD8 cytotoxic T lymphocytes
+
+
CD8 T cells are critical for pathogen clearance, where they contribute to the resolution of HBV and HCV
[42]
infections in the liver [42,43] . Guo et al. study confirmed that Fas/FasL interactions might suppress antitumor
+
immune responses via turnover of CD8 T cells. In addition, a series of immunoregulatory elements such
as IL-10, IL-2, VEGF and indoleamine-2,3-dioxygenase (IDO) play an important role in inhibiting tumor-
+
+
associated antigen (TAA)-specific CD8 T cell responses [42,44,45] . It has been proven that CD14 DCs inhibit