Page 9 - Read Online

Page 4 of 14 Monge Bonilla et al. Hepatoma Res 2020;6:68 I http://dx.doi.org/10.20517/2394-5079.2020.58

IMMUNE EVASION MECHANISMS OF HCC ASSOCIATED WITH HBV/HCV
Following persistent chronic liver inflammation due to HBV and HCV infection and immune imbalances,
HCC develops with specific immunological features. There were 22% of 196 HCC samples displaying high
or moderate levels of lymphocyte infiltration from an analysis of TCGA HCC samples, with high expression
of immunosuppressive molecules and enriched Tregs, resting DCs and undifferentiated M0 macrophages
compared to normal livers. This indicates an immunosuppressed microenvironment in this group of HCC
[63]
patients. HBV/HCV infection status appeared not to be significantly associated with these observations .
+
There was also T-cell enrichment with heterogenetic clonal expansion of CD8 T-cell populations with
exhausted characteristics based on the sequencing of T-cell receptors (TCR) in TILs [64,65] . Interestingly, a
further study showed CD8+ resident memory cells were enriched in HBV-related HCC with higher PD-1
[66]
expression and functionally more exhausted than non-virus-related HCC . Increased numbers of CD14+
[67]
HLA-DR−/low MDSCs were found to be related to HCC progression . Furthermore, infiltrating MDSCs
[67]
not only suppress T-cell proliferation via arginase to deplete arginine , but also promote Treg expansion
[67]
through the production of IL-10 and TGF-β, and inhibit effector T cells through PD-L1 . In addition,
high IL-10 secretion by MDSCs results in the skewing of resident tumour-associated macrophages (TAMs)
[68]
and monocytes to an immunosuppressive phenotype . They release TGF-β and VEGF to promote
tumour growth and development, promoting cancer stem cells and metastasis , stimulating Tregs, and
[69]
[70]
[64]
suppressing NK cells . Noticeably, Tregs are enriched in HCC . This enrichment is prominent in HBV-
related HCC with greater expression of PD-1 and increased suppressive function, which represents a
more immunosuppressive and exhausted immune microenvironment in HBV-related HCC compared to
[66]
the non-virus-related HCC . The increased Tregs not only suppressed HBV antigen-specific immune
[71]
responses, but also suppressed HCC tumour antigen-specific immune responses . DCs are severely
dysregulated in HCC, with a subset of CD14+ DCs expressing high levels of CTLA-4 which indicates an
[72]
inhibitory phenotype . In addition to these immune cells, several other stromal cells, such as NK cells,
endothelial cells and cancer-associated fibroblasts, orchestrate immune evasion in HCC . For example,
[73]
endothelial cells in cancer tissues reportedly produce the C-X-C motif chemokine ligand 12, facilitating the
[74]
recruitment of MDSCs . Together, these data suggest that HCC is an immunogenic malignancy, rendering
it an attractive target for immunotherapy [Figure 1].
CURRENT IMMUNOTHERAPY OF HBV- AND HCV-RELATED HCC
Immunotherapy, specifically immune checkpoint inhibition, has been considered a useful treatment
option for HCC, evidenced by both pembrolizumab (anti-PD-1) and nivolumab (anti-PD-1) with or
without ipilimumab (anti-CTLA4) approved as second line therapy, and atezolizumab (anti-PD-L1) with
bevacizumab approved as first line treatment options. In addition to immune checkpoint inhibitors (ICIs),
several immunotherapy approaches are in development, including antibodies targeting specific tumour-
associated antigens (TAAs), adoptive cell therapy, vaccination based on TAAs or mutation-associated
neoantigens (MANAs) and oncolytic viruses. Although the infection of HBV and HCV is highly associated
with HCC development, data on response outcomes specifically in this population included in trials is
scarce.

IMMUNE CHECKPOINT INHIBITORS
Tremelimumab, a CTLA-4 inhibitor, was the first immune checkpoint inhibitor (ICI) that showed
encouraging results in patients with advanced HCC. In a phase II study including patients with advanced
HCC and chronic HCV infection, tremelimumab showed an objective response rate (ORR) of 17.6%, a
disease control rate (DCR) of 76.4%, a median time to progression of 6.48 months, and a median overall
[75]
survival (OS) of 8.2 months . Importantly, in this study, tremelimumab also exhibited antiviral effects
evidenced by a significant decline in viral load. There were no treatment-related deaths and the treatment
was mostly well tolerated.