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Page 2 of 12 Ni et al. Hepatoma Res 2020;6:25 I http://dx.doi.org/10.20517/2394-5079.2020.14
[2]
B virus while in the West, nonalcoholic-associated steatosis seems to be one of the main causes . In the
early stages of HCC, hepatic resection or liver transplantation is first-line treatment with a high probability
of a recurrence-free postoperative course. Sorafenib, a broad tyrosine kinase inhibitor, is standard treatment
[3]
for advanced or metastatic HCC . HCC is also known as an immunogenic tumor, which develops in
chronically inflamed livers from both viral and non-viral causes. This inflammation promotes tumor
[4]
development and is related with increased tumor immunogenicity . As such, immunotherapy might be a
more appropriate treatment strategy for HCC.

The liver, however, plays a pivotal role in host defense and the maintenance of immune competence. It is
known to have an intrinsic,immunosuppressive microenvironment, which may serve as a major barrier
[4]
to cancer immunotherapy . Moreover, the low expression levels of tumor-associated antigens result in
weaker T cell activation and in turn, tumor infiltration, which results in less efficient tumor control and
consequently, a poorer clinical outcome. Thus, therapeutic strategies need to be developed against the HCC
[5]
tumor suppressive microenvironment, which is involved in lowering the efficacy of immunotherapy .

Although treatment strategies for patients with intermediate and advanced HCC are quite limited, an
[6]
attractive option is immunomodulation therapy . Current HCC immunotherapy approaches include
immune checkpoint inhibitor antibodies (ICB), adoptive cell transfer (ACT), dendritic cell-based vaccines
and oncolytic therapy but only ICB (anti-PD-1/PD-L1 antibodies) have been approved by the FDA as
second-line treatment for HCC patients . The major impediment to the development and success of
[7]
[6]
immunotherapy in HCC patients is the intrinsic immunosuppressive microenvironment . In this review
article, we summarize recent advances in, and the future of immunotherapy for HCC and discuss their
combination for the treatment of HCC patients.

TUMOR MICROENVIRONMENT
The tumor microenvironment (TME) is widely studied for the identification of novel therapeutic targets.
The HCC TME consists of cancer and stromal cells, including hepatic stellate cells, cancer-associated
[8]
fibroblasts, immune cells and endothelial cells, which interact with and affect the growth of the tumor .
The immune landscape of HCC is heterogeneous. By using 10×-single cell RNA-sequencing, Zhang and
+
colleagues found that intratumor LAMP3 mature dendritic cells (DCs) had the capacity to migrate from
[9]
+
tumors to lymph nodes . LAMP3 DCs also expressed diverse immune-relevant ligands and possessed the
ability to regulate several types of lymphocytes. Macrophages in tumors displayed distinct transcriptional
states and tumor-associated macrophages (TAMs) were correlated with a poor prognosis. Myeloid cells
[9]
in ascites were predominantly of tumor origin while lymphoid cells originated from blood . Through
[10]
time-of-flight mass cytometry, Chew et al. found that the HCC TME was enriched in regulatory T cells,
+
tissue resident memory CD8 T cells, resident natural killer cells, and TAMs. Tissue resident memory
PD-1 CD8 T cells were the major T cell subset responsive to PD-1 blockade. Zhang et al. found that
+
+
[11]
B cell infiltration of tumors was significantly impaired during tumor progression but tumors with a high
density of B cell infiltration correlated with better clinical outcomes. It was also found that there was a
+
high number of TIM-1 Breg cell infiltrating the tumors of HCC patients [12,13] . These infiltrating Breg cells
expressed IL-10 and had high suppressive activity against CD8 and CD4 T cells. B cells, except Breg
+
+
cells, may contribute to tumor regression. Thus, using a selective reagent to inhibit suppressive B cells may
be a viable strategy. By improving understanding of the immunologic components of the TME and its
corresponding interactions at the biological and molecular levels, more effective immunotherapies for HCC
can be designed.
ADVANCEMENT OF ICB
The mechanism of action of ICB is to stimulate or normalize the immune system of cancer patients by
targeting negative regulators of T cell signaling pathways. FDA approved PD-1/PD-L1 inhibitor antibodies