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Page 2 of 13 Li et al. Hepatoma Res 2020;6:15 I http://dx.doi.org/10.20517/2394-5079.2019.34

patients with advanced HCC. The first-line agent sorafenib modestly extends the survival in advanced HCC
[3]
by about 3 months . Lenvatinib has been approved for HCC treatment based on the results of a randomized
phase III trial, in that lenvatinib is non-inferior to sorafenib in overall survival assessment in patients with
[4]
advanced HCC, with similar safety and tolerability profiles as sorafenib . Regorafenib and cabozantinib
have been approved as second-line options for patients with progressive HCC despite on-going sorafenib
[5-7]
treatment, in that they improve overall survival in such patients . Nonetheless, the survival benefit from
the TKIs is limited and unexpected. Therefore, novel clinical therapies are urgently required for treatment of
early-stage and advanced HCC. Recently, immunotherapy with immune checkpoint blockade and adoptive
immune cell transfer has been clinically tested in various types of cancers, which provides a novel therapeutic
strategy for difficult-to-treat HCC cases. The present review aims to summarize the characteristics and
+
roles of natural killer (NK) cells and CD8 T cells during HCC development, describe the frontiers of
immunotherapy for advanced HCC based on immune checkpoint inhibitors (ICIs) and adoptive cell transfer
(ACT), and discuss their limitations and scope for future improvement.

+
NK CELLS AND CD8 T CELLS IN HCC
[8,9]
The liver contains diverse types of immune cells such as T cells, NK cells, B cells, NKT, and Kupffer cells .
However, the liver is a tolerogenic immune organ in the physiological state, in that the liver remains tolerant
to stimuli from the hepatic artery and portal vein, such as bacterial products, environmental toxins, and
food antigens, to avoid tissue damage [10,11] . This immune-tolerant microenvironment of the liver contributes
[12]
to the immunoescape of HCC . Studies have extensively discussed the properties and contribution of
[13]
immunosuppressive cells during HCC progression . However, to our best knowledge, the characteristics and
+
contribution of the two most important anticancer immune cells in the liver - NK cells and CD8 T cells - have
not been well-documented.

NK cells in HCC
Innate lymphoid cells (ILCs) function as the first line of immune defense against infections and cancers.
Paralleling with T cell subsets, ILCs comprise NK cells, ILC1, ILC2, and ILC3, amongst which the NK and
ILC1 cells are abundant in the liver [14,15] . Unlike helper ILC subsets, NK cells are classified as a cytotoxic
ILC subset because of their direct killing of cancer cells and infected cells via cytotoxicity and cytokine
[16]
secretion . NK cells express activating receptors such as CD16, NKp30, NKp44, NKp46, NKp80, NKG2D,
CD244, CD226; cytokine receptors such as IL-2R, IL-28R, IL-12R, IFNR, IL-15R, IL-18R, IL-1R8, IL-10R,
and TGFR; and inhibitory receptors such as NKG2A, KLRG1, KIRs, TIGIT, TIM3, Siglecs, PD-1, LAG3,
A2AR, LAIRs, and ILTs [17,18] . The activation of NK cells is determined by the net value of activating signal
strength determined by the competition between activating and inhibitory receptors [17,19] . The abundance
and activity of NK cells are modulated by multiple signals within the tumor microenvironment, which
significantly influence cancer development. Compared with healthy controls, HCC patients have a dramatic
reduction of tumor-infiltrating NK cells; their abundance in HCC tissues is positively correlated with patient
[20]
survival . NK cells in the HCC tissues of patients with advanced HCC show dysfunctional or exhausted
[20]
state , suggesting that NK-cell exhaustion contributes to HCC progression. The regulators for NK cell
exhaustion have been extensively investigated. For example, the up-regulation of inhibitory receptors on
[21]
NK cells leads to NK-cell exhaustion and predicts poor prognosis in HCC patients . TGF-β and IL-10
promoted NK-cell exhaustion in HCC [22,23] . Hypoxia-induced mitochondrial fragmentation limits NK-
[24]
cell anticancer activity . Additionally, immunosuppressive cells such as myeloid-derived suppressor cells,
monocyte/macrophage, and HCC-associated fibroblasts in intratumor tissues of HCC contribute to NK-
cell exhaustion [25-27] . The plasticity of NK cell activity provides the foundation of NK-cell-based cancer
immunotherapy. Immunotherapeutic drugs triggering NK-cell activation are being developed and assessed
in pre-clinical and clinical trials. Nevertheless, it is still crucial to decipher the mechanisms by which NK
cells undergo exhaustion in patients with advanced HCC, in order to offer more patient benefits in terms of
effective reinvigoration of NK-cell anticancer activity and precision therapy in HCC.