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Page 2 of 15 Missale et al. Hepatoma Res 2018;4:22 I http://dx.doi.org/10.20517/2394-5079.2018.72

Hepatocellular carcinoma (HCC) initiation and progression are multi-step processes profoundly influenced
by the interplay between hepatocytes and immune cells. Immunotolerance is disrupted in chronic liver
disease where persistent infections with hepatitis B virus (HBV) or hepatitis C virus (HCV), accumulation
of fat, exogenous toxic substances (alcohol) or iron overload (haemochromatosis) enhance inflammatory
signals triggering a cycle of cell death/regeneration and compensatory fibrosis, leading to liver cirrhosis, that
represents a pre-neoplastic state. Chronic inflammation induces the accumulation of reactive oxygen species,
generating epigenetic changes and chromosomal instability that contribute to tumor initiation, with expres-
sion of neo-antigens and/or deregulation of the expression of oncofetal and cancer testis antigens such as
[3]
alpha-fetoprotein (AFP), glypican-3 (GPC-3), melanoma-antigen gene (MAGE) family, NY-ESO.1 .

IMMUNE RESPONSE AGAINST HCC
Cytotoxic T cells (CTLs) recognizing tumor-associated antigen (TAAs) have been detected in HCC patients
[3-5]
and their abundance is associated with patient survival . CD8+ and CD4+ T cells were shown to accumu-
late in early HCC with a progressive decrease in late stages, that represents a negative predictor for disease
[3,6]
outcome . TAA-specific CD8+ T cells from peripheral blood produce interferon (IFN)-γ upon stimula-
tion, but tumour-infiltrating lymphocytes fail to do so, indicating the progressive exhaustion of intratumour
[3]
CD8+ T cells . Exhausted T cells are characterized by impaired effector function and sustained expression
of co-inhibitory receptors, and cannot mature into memory T cells.

NK cells account for 25%-50% of the total number of liver lymphocytes and are strongly implicated in the
anti-tumor response. Impaired effector function of NK cells was reported in HCC and related to disease out-
[7,8]
come . Several mechanisms have been implicated in NK cell dysfunction: the genetic make-up of KIR NK
cell receptors [9-11] , a higher percentage of NK-cells co-expressing inhibitory NKG2A and activating NKp30-
NKp46 receptors [12,13] , myeloid-derived suppressor cells (MDSCs)-mediated suppression [14-16] , increased prev-
[17]
alence of a dysfunctional CD11bnegCD27neg NK-cell subset .

Among factors contributing to the immune suppressive microenvironment of HCC are cell-mediated
mechanisms, the secretion of cytokines and chemokines by tumor, stromal, and infiltrating cells, and the
immunoediting of TAAs [18,19] . In this context, adaptive immune response exerts a dual role with seemingly
opposite functions, being part of the inflammatory environment that likely plays a major role in tumor pro-
[20]
motion, but hampering tumor dissemination through cytotoxic function against transformed cells .

MECHANISMS OF IMMUNE IMPAIRMENT IN HCC
The development and progression of HCC evolve through a dynamic interaction between tumor cells, non-
parenchymal resident cells such as Kupffer cells (KCs), HSCs, LSECs, infiltrating immune cells and immune
mediators. All these elements participate in the tumor microenvironment that exerts a profound influence
on the evolution of disease. The many factors that co-operate to the immune landscape of HCC represent
potential targets for therapeutic intervention.

Immunosuppressive molecules
Immune checkpoints are coinhibitory molecules that control the duration and the strength of immune re-
sponse to prevent over-activation of T cells. This class of molecules includes CTLA-4, PD-1, TIM-3, lympho-
cyte activation gene 3 protein (LAG-3) and B and T lymphocyte attenuator (BTLA). Immune checkpoints are
exploited by tumors as mechanisms of immune evasion and may therefore become major targets of immune
therapeutic strategies.

CTLA-4 is expressed by activated T cells and by Treg cells. It competes with the activating molecule CD28
[21]
for binding CD80 and CD86 and activates Tregs [22,23] .