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da Fonseca et al. Hepatoma Res 2019;5:37 I http://dx.doi.org/10.20517/2394-5079.2019.012 Page 3 of 13

Kupffer cells, which are stationary macrophages in the liver sinusoids, contribute to immune tolerance by
producing inhibitory cytokines such as IL-10 and prostaglandins and by expanding inhibitory regulatory
T cells. Kupfer cells also plays a major role in the clearance of gut-derived endotoxins from the portal
[17]
circulation .
Tolerance-inducing cells, such as inhibitory CD4+CD25+FoxP3+ T regulatory (Treg) cells, are increased
[18]
in tumor tissue and peripheral blood of HCC patients . Tregs can impar the effector function of intra-
tumoral CD8+ T cells by several mechanisms, such as IL-10 and transforming growth factor (TGF) beta
[19]
production .

Neutrophils have been shown to induce tumor cell proliferation and stimulate angiogenesis through the
[20]
secretion of cytokines . Infiltrating neutrophils have been shown to recruit Tregs in animal HCC models
and the number of neutrophils in HCC infiltrate is reported to be a negative prognostic factor in HCC
[21]
patients submitted to resection .

Myeloid-derived suppressor cells (MDSCs) are myeloid progenitor cells that acts as suppressor of Natural
Killer (NK) cells and T cell effector function in the tumor microenvironment mediated by the expression
of arginase, that depletes arginine, which is essential for T cell proliferation and also by the release of
reactive oxygen species [22,23] . The MDSC subset has been reported as a prognostic factor for HCC recurrence
[24]
after local treatment .
Besides the activity of these immune cells, the liver micro-environment overexpresses immune checkpoint
molecules, which can downregulate immune responses against tumor cells. PD-1/PD-L1 expression is
observed not only in Kupffer cells, but also in tumor infiltrating lymphocytes. An association between
[25]
PD-1 expression by T CD8+ lymphocytes and poor prognosis in HCC patients is reported . T-cell
immunoglobulin and mucin-domain-containing molecule-3 is expressed by cells from innate and adaptive
immune system and interacts with several ligands such as Galectin 3, which is expressed in liver tissue.
Evidence indicates that Galectin-9 inhibits T-cell responses, acting as an immunosuppressive factor.
Lymphocyte-activation gene 3 (LAG3) is a membrane protein that is expressed in activated T-cells and
suppresses dendritic cells function. LAG3 acts symmetrically with PD-1 to promote cancer evasion from
[26]
immune recognition .

The hepatic chemokine profile also plays a substantial role in modulating immune response. It has been
demonstrated that immunosuppressive cytokines such as IL-4, IL-5 and IL-10 are upregulated, while
some pro-inflammatory cytokines such as TNF and IL-1 are downregulated, what can facilitate HCC
[27]
progression .
Tumor mutational burden is a measurement of mutations carried by tumor cells that seems to be correlated
with cytotoxic T cells infiltration and better response to immune-checkpoint inhibitors (ICI) [28,29] . The
mutational burden typically translates into a higher neo-antigen load, and therefore a higher chance that
an antigen capable of stimulating an immune reaction is expressed on the tumor cell surface. Nevertheless,
HCC ranks only as a medium mutated tumor, with an average of 5 somatic mutations per megabase,
corresponding to approximately 60 non-synonymous substitutions within expressed genes. This accounts
for a likely lower neoantigen burden comparing to melanoma, for example .
[30]
The current research activity on immunotherapy for HCC are mainly based on targeting the above-
mentioned mechanisms. The complexity of immune system and the dismal prognosis of HCC are barriers
for the translation of basic research from bench-to-bedside. In this regard, the development of cancer
vaccines, adoptive cellular therapies, ICI and combinations of immunotherapy with other agents or with
different treatment modalities are being developed and tested in the clinical setting.