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Missale et al. Hepatoma Res 2018;4:22 I http://dx.doi.org/10.20517/2394-5079.2018.72 Page 3 of 15

PD-1 is expressed by activated T and B lymphocytes, NK cells, Treg cells, MDSCs, monocytes and DCs [24,25] .
The expression of PD-1 is induced by several cytokines including IFN-γ [26,27] . Under hypoxic conditions,
production of hypoxia-inducible factor (HIF)-1 induces the expression of PD-L1, the PD-1 ligand, in MDSCs
and tumor cells [22,27,28] . The interaction between PD-1 and PD-L1 inhibits T cell effector function and leads to
[29]
T cell exhaustion . The immune infiltrate of HCC is enriched in PD1+ CD8+ cells and their abundance is
[30]
associated with disease prognosis . The expression of PD-L1 in HCC has also been reported as a prognostic
factor of shorter disease-free and overall survival [31-34] .

TIM-3 is a transmembrane protein expressed on various immune cells and interacting with multiple ligands
[35]
among which galectin-9, a soluble protein expressed by several tissues including liver that negatively
[37]
[36]
regulates Th1 cell function . In addition, TIM-3+ Treg cells exhibit enhanced suppressor activity . A
role of the TIM-3/galectin-9 pathway in the determination of HCC-infiltrating T cell dysfunction has been
[38]
reported .
LAG-3 binds MHC class II molecules with high affinity [25,39] thus reducing co-stimulatory function of DCs.
[40]
[41]
LAG-3 is upregulated upon activation of T cells and is a marker of exhausted T cells . Its activation and,
as a consequence, its blockade are synergistic with PD-1 [42,43] . BTLA is upregulated on activated lymphocytes
[44]
and on tumour-specific CD8+ T cells in patients with cancer . High expression of the BTLA ligand HVEM
(herpesvirus entry mediator) has been reported in patients with HCC and is associated with reduced
[45]
lymphocyte infiltration and poorer prognosis .
Cytokines are membrane-bound or secreted proteins involved in the regulation of immune cell function,
inflammation and angiogenesis. Their pleiotropic roles include pro- and anti-inflammatory functions. CD4+
T helper cells produce either Th1 cytokines [e.g., interleukin (IL)-1, IL-2, IL-12, IL-15, tumor necrosis factor
(TNF)-α and IFN-γ] usually defined pro-inflammatory, or Th2 cytokines (e.g., IL-4, IL-8, IL-10 and IL-5)
[46]
mainly exerting anti-inflammatory functions .
Increased levels of IL-10 and TGF-β and reduced levels of IFN-γ have been detected in plasma from HCC
[47]
patients . In liver tissue IL-10 is produced by DCs, KCs, HSCs, LSECs, MDSCs and T cells, inducing tol-
[50]
erance [48,49] . Tolerogenic effect of IL-10 is linked to inhibition of CD4+ T cell activation and, as a conse-
[51]
quence, of cytotoxic CD8+ T-cell function . In addition IL-10 further interferes with T cell activation by
[52]
[53]
downregulating the expression of MHC-II and CD80/CD86 on APCs and of NF-kB , a transcription
factor strongly implicated in inflammatory responses. Despite its immunosuppressive activity in the context
of inflammation, several studies report an immune-stimulatory role of IL-10 on CD8+ T-cell and NK-cell
cytotoxic activity in experimental tumor models [54-56] .
TGF-β, produced by parenchymal and non-parenchymal liver cells, is implicated in the maintenance of liver
[57]
immune homeostasis and may exert a suppressive function towards anti-tumor immune reaction. TGF-β
inhibits the expression of the transcription factors T-bet and GATA3, essential for the conversion of naive
CD4+ T cells into Th1 and Th2 CD4+ T cells, respectively [58,59] . Conversely, TGF-β induces the differentiation
of naive CD4+ T-cells into Tregs, inhibits the differentiation of naive CD8+ T cells to effector cells [60,61] and
[62]
decreases perforin and IFN-γ expression, further impairing cytotoxic CD8+ T-cell activity .
Cell-mediated immune suppression
Immune evasion of tumor cells may be linked to altered antigen processing and presentation, deriving from
[63]
HLA class I downregulation or from 2 microglobulin mutation/deletion . HLA class I expression is essen-
[64]
tial for antigen presentation to CTLs and for tumor cell recognition by NK cells . Tumor cell elimination
by NK cells may be also impaired by decreased expression of the NKG2D ligand ULBP1 that correlates with
[65]
early recurrence of HCC . Another mechanism of HCC immune evasion from NK cell killing has been