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Li et al. Hepatoma Res 2020;6:15 I http://dx.doi.org/10.20517/2394-5079.2019.34 Page 3 of 13

NK cells have been reported to account for 20%-40% of human hepatic lymphocytes and 10%-20% of murine
[28]
hepatic lymphocytes, more than half of which bona fide comprise ILC1 or liver-resident NK cells . The
observations from the parabiosis model show that the liver contains conventional NK cells and liver-resident
[29]
NK cells , further supported by the findings that hepatic irradiation could persistently eliminate liver-
[30]
resident NK cells . Early evidence has shown that liver-resident NK cells expressed higher levels of CD160,
[29]
CD69, CD44, CXCR3, CXCR6, TRAIL, FasL, GM-CSF, and TNF-α . CXCR6 is required for the retention of
[31]
+
liver-resident NK cells within the liver . CD8 T cells promote liver-resident NK cell maturation through the
[33]
[32]
CD70-CD27 axis . Liver-derived TGF-β maintains the property of liver-resident NK cells . Functionally,
[29]
[34]
liver-resident NK cells were originally found to mediate skin-contact inflammation . Zhou et al. reported
that liver-resident NK cells inhibited T cell antiviral activity via PD-L1 during viral infection. Additionally,
[35]
+
liver-resident NK cells can suppress autoimmune cholangitis by limiting the expansion of CD4 T cells .
These findings suggest that liver-resident NK cells play versatile roles in liver diseases. Human liver-resident
+
hi
+
+
lo
+
-
NK cells are CD56 bright Eomes Tbet Hobit TIGIT CD69 CXCR6 CD49e ; express higher levels of
[36]
NKG2D, NKp46, TRAIL, and FasL; and possess cytotoxicity against HCC cells . However, liver-resident
[37]
NK cells within the HCC tissue down-regulate NKG2D . Moreover, liver-resident NK cells express more
[38]
types of inhibitory receptors such as PD-1, CD96, and TIGIT . Therefore, liver-resident NK cells undergo
exhaustion during HCC progression. Fortunately, IL-15 could recover HCC-induced liver-resident NK-cell
[37]
dysfunction . In addition, the mTOR inhibitor - everolimus - enhances their anticancer activity through
[39]
upregulation of TRAIL . Thus, liver-resident NK cells have the potential for application in HCC therapy,
although the complete underlying mechanism of liver-resident NK cells’ exhaustion remains unclear.
+
CD8 T cells in HCC
+
+
+
The abundance of tumor-infiltrating CD8 T cells and the frequency of IFN-γ CD8 T cells were
associated with improved survival of HCC patients [40,41] . CD8 T cells were enriched in early-stage HCC,
+
but progressively reduced with tumor progression, accompanied with increased expression of checkpoints
[42]
+
on tumor-infiltrating CD8 T cells . Therefore, CD8 T cells in HCC tissues progressively underwent
+
functional compromise during cancer progression, characterized by high levels of immune checkpoints,
+
low effector cytokines, and impaired cytotoxicity and proliferation. In detail, however, CD8 T cells in HCC
[43]
high
+
tissues expressed different PD-1 levels and displayed different anticancer capacity . Among PD-1 CD8
[44]
T cells, 4-1BB PD-1 CD8 T cells displayed stronger anticancer activity and proliferative potential . In
+
high
+
+
+
recent times, several studies have reported that TCF-1 PD-1 T cells sustained the stemness and response
to immune checkpoint blockade in certain types of cancers [45,46] . Therefore, the identification of functional
+
tumor-infiltrating CD8 T cells for immunotherapy will likely benefit clinical outcomes and promote
precision medicine for HCC patients.
The systemic, local, cellular, and molecular mechanisms of T-cell exhaustion in HCC have been
extensively investigated. The hepatic inflammatory microenvironment had been confirmed to be critical
[48]
[47]
for HCC development . Lim et al. found that HBV-related HCC microenvironment displayed more
immunosuppression than non-viral-related HCC microenvironment, indicating increased difficulty in
the immunotherapy of HBV-related HCC. Hepatoma cells, LSECs, suppressive immune cells, inhibitory
+
[49]
receptors, and cytokines have been found to trigger tumor-infiltrating CD8 T-cell exhaustion . For
instance, myeloid-derived suppressor cells and T regulatory cells in HCC tissues had been found to impair
+
[51]
[50]
T-cell functionality . The inhibitory cytokine - IL-35 - dampened CD8 T cells activity in HCC patients .
14-3-3ζ, a suppressor of apoptosis, is highly expressed in HCC and promotes epithelial-mesenchymal
[53]
[52]
transition of HCC cells . Wang et al. reported that 14-3-3ζ delivered by HCC-derived exosomes
contributed to impaired anticancer activity of CD8 T cells. The thymocyte selection-associated high mobility
+
group box (TOX) transcription factor belongs to an evolutionarily conserved DNA-binding protein family
[54]
and regulates the development of T cells . Recently, several studies have confirmed that TOX was critical
+
+
for CD8 T cell exhaustion [55,56] . Moreover, it was found that TOX could promote CD8 T-cell exhaustion in