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

ascribed to the impaired interaction between NKG2D and its stress-induced ligands MIC-A and -B, that are
upregulated on tumor cells. In advanced HCC, tumor cells escape from NK-mediated immunosurveillance
through shedding of MIC-A that induces downregulation of NKG2D thus affecting NK cell effector func-
[66]
tion .
Together with shared oncofetal and cancer-testis antigens, driver and passenger mutations occurring in the
tumor cell genome can generate tumor-specific neoantigens that can contribute to tumor immunogenicity
[67]
and represent potential immunotherapeutic targets . Like viral antigens, TAAs undergo immune selective
pressure that triggers the selection of resistant variants with survival advantage due to lower immunogenic-
ity or immunosuppressive activity. The genetic instability of transformed cells favors this phenomenon of
[68]
antigenic immunoediting . Immune escape may also result from the secretion by HCC cells of immuno-
suppressive molecules as TGF-β, IL-10, indoleamine 2,3-dioxygenase (IDO), arginase, or from decreased co-
[69]
stimulatory/increased inhibitory checkpoint signaling .
[70]
MDSCs represent a heterogeneous population of immature myeloid cells that share suppressive func-
[73]
[74]
tions [71,72] through different mechanisms: depletion of arginine and cysteine that are essential for T cell
[75]
function, and release of reactive oxygen and nitrogen species that disrupt TCR signaling . In addition,
MDSCs promote tumor progression through neo-angiogenesis due to vascular endothelial growth factor
[76]
(VEGF) production, and through enhanced tumor cell survival and dissemination .
[14]
In HCC MDSCs have been shown to inhibit NK cell function via NKp30 receptor or through membrane-
[15]
[77]
bound TGF-β and to induce Tregs by IL-10 and TGF-β production . A specific CD14pos HLA-DRneg/
low MDSC subset increased in tumor tissue and peripheral blood of patients with HCC was implicated the
[77]
induction of Tregs . The multiplicity of this MDSC subset was reported as a negative prognostic factor for
[78]
[80]
[79]
HCC recurrence after resection , radiation therapy , hepatic arterial infusion chemotherapy , as well as
[81]
for tumor progression .
MDSCs are recruited by cytokines and chemokines secreted by tumor cells [72,82] . Senescent hepatocytes were
shown to recruit immature MDSCs able to differentiate into macrophages through C-C motif chemokine
ligand 2 (CCL2)-CCR2 signaling, thus preventing HCC initiation. However, in the presence of HCC, im-
mature MDSCs do not differentiate thus contributing to the immunotolerant environment through NK-cell
[83]
inhibition .
[84]
Kupffer cells (KCs), the liver resident macrophages, represent about 80% of the macrophages in the body
[85]
and contribute to the maintenance of liver immune tolerance through their anti-inflammatory function
[86]
exerted by upregulation of PDL-1 expression, downregulation of costimulatory molecules , secretion of
[88]
[87]
IDO and IL-10 . In human HCC, Kupffer cells in the peritumoral margin express higher levels of PD-
L1 compared to non-tumorous liver, thus inhibiting CD8+ T cell effector function. Blockade of PD-1/PDL-1
[89]
interaction in vitro was able to restore T cell killing in vitro .
The HCC immune microenvironment induces the polarization of macrophages towards the M2 phenotype
typical of the tumour-associated macrophages (TAMs). M2 macrophages are characterized by producing
[90]
high levels of IL-10 that induce Treg expansion and impairs NK cell activation . In addition, TAM promote
tumor angiogenesis and dissemination [91,92] . A distinct subset of monocytes expressing TIE2 with enhanced
pro-angiogenic properties has been described in peripheral blood and in tumor infiltrate [93-95] . In human
[96]
HCV-related HCC this monocyte subpopulation was related to neo-angiogenesis and to prognosis .

Tregs are CD4+ T cells expressing CD25, CTLA-4, CD62L and FoxP3. Tregs exert inhibitory functions
through multiple mechanisms, among which IL-2 depletion by CD25 (IL-2 receptor), competition with