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Missale et al. Hepatoma Res 2018;4:22 I http://dx.doi.org/10.20517/2394-5079.2018.72 Page 5 of 15

[97]
CD28 by CTLA-4, CTLA-4-mediated downregulation of CD80 and CD86 , expression of TGF-β and IL-
[98]
[99]
10 . The recruitment of Tregs in HCC occurs via the CCR6-CCL20 axis and CCL22 induction by tumor
cell-secreted IL-1α [100] . In addition, FoxP3 upregulation and conversion of CD4+ T cells into Tregs may be
fostered by poor stimulation of naive CD4+ T cells combined with TGF-b signalling by tumor cells [101] .

In patients with HCC, FoxP3+ Tregs are increased both in peripheral blood [102,103] and in tumor tissue [31,103] ,
and the abundance of tumour-infiltrating Tregs is associated with intra-tumoral macrophages [104] . Several
studies support a negative correlation between Treg infiltrate and effector function of intra-tumoral CD8+ T
cells [47,103] and a direct role of Treg infiltration over disease progression and overall survival [99,103-105] .

HSCs play a role in HCC progression through release of hepatocyte growth factor [106] and induction of both
MDSC [107,108] and Treg accumulation [109] . In addition, HSCs can also directly induce T cell apoptosis through
PD-L1 expression [110] . Activated HSCs interact with monocytes inducing an immunosuppressive environ-
ment and contributing to poor prognosis in HCC [111] .

NKT cells are a heterogeneous group of T lymphocytes sharing properties of both T cells and NK cells. NKT
cells recognize glycolipid antigens via an invariant TCR α chain. The CD4+ iNKT-cells have been found to
be enriched in intrahepatic malignant tumors [112] . Intra-tumoral CD4+ iNKT-cells produce Th2 cytokines
that can inhibit expansion of tumor antigen-specific CD8+T-cells [112] . Consistent with this view, we observed
[31]
that enrichment of iNKT cells in HCC infiltrate was predictive of shorter TTR .

Several other infiltrating or stromal cell types co-operate to the generation of immunosuppressive tumor
microenvironment [113] . A population of PD-1-positive B cells has been identified in HCC. This cell subset was
shown to suppress anti-tumor T cell response through PD-1-PDL-1 interaction and to promote disease pro-
gression [114] .

LSECs express PDL-1 and contribute to the immunosuppressive environment by TGF-β-dependent induc-
tion of Tregs [115] . A subset of CD14+ DCs with suppressor function has been detected in patients with HCC.
These DCs expressing high levels of CTLA-4 and PD-1 inhibit T-cell response through production of IL-
10 and indoleamine-2,3-dioxygenase (IDO) [116] . Th17 cells are a IL-17-producing CD4+ T cell subset that
plays an important role in the maintenance of mucosal barriers. Increased frequency of CCR4+CCR6+,
but not CCR4-CCR6+ Th17+ cells was reported in peripheral blood from patients with HCC. The
CCR4+CCR6+Th17+ cell subset was shown to impair CD8+ T cell effector functions [117] . Neutrophils release
cytokines that contribute to the tumor microenvironment either promoting or inhibiting tumor progres-
sion [118] . In HCC, neutrophils have been shown to recruit macrophages and Tregs fostering tumor progres-
sion and resistance to sorafenib [119] . Tumor-associated fibroblasts (TAFs) are essential components of the
HCC microenvironment and support tumor progression through the secretion of various cytokines and
growth factors. HCC-associated TAFs inhibit NK-cell function by secreting prostaglandin E2 and IDO [120] .
In addition, TAFs have been shown to release IL-6 and SDF-1a (CXCL-12), which induce MDSC generation
and activation thus impairing anti-tumor immune response [121] .

IMMUNOTHERAPEUTIC STRATEGIES
The scenario of the immune mechanisms operative in HCC is quite complex with liver intrinsic immuno-
suppressive environment associated with several mechanisms common to solid tumors. Physiologically, with
the exception on anecdotal cases the tumor will escape, avoid, adapt to or overcome the immune mediated
mechanism aimed at rejection of transformed cells. From the therapeutic perspective the problem has been
approached by several strategies focusing on potentiation of different effector immune cells, tumor antigens
made immunogenic, block of negative costimulatory pathways or immunosuppressive cells or soluble me-
diators.