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Page 2 of 3 Dai. Hepatoma Res 2019;5:33 I http://dx.doi.org/10.20517/2394-5079.2019.26

promoting HCC progression by recruiting TAMs and MDSCs to the tumor microenvironment, thus
+
inhibiting CD8 T cell function and further facilitating immune escape.

In this issue, the authors first demonstrated elevated abundance of A3B in HCC patients due to
overactivation of the non-classical NF-κB pathway and direct transcriptional regulation by RelB. Taking
advantage of both immunocompetent and immune-deficient mouse HCC models, they revealed that A3B
activated HCC initiation through modulation of the immune system as A3B exerted its carcinogenic
function only in mice with complete immune system, which was accompanied by increased secretion of
CCL2, IL-34 and BMP7 and the subsequent accumulation of TAMs, MDSCs and Programmed cell death
+
1(PD1) CD8 T cells.
After establishing the impact of hepatocyte-intrinsic A3B on immunological environment in HCC
development, Wang and his colleagues performed a series of analyses to investigate the molecular basis
of this phenomenon. They found out that A3B inhibited PRC2 activity through both interference of its
binding affinity and attenuating its enzymatic activity, while PRC2 has been reported to be indispensable
in the methylation of H3K27 and regulate chemokine expression [9,10] . Bioinformatic analyses showed a
highly overlapping cohort of target genes, whose expression levels altered in inverse correlation upon
exogenous A3B expression and H3K27me3. Experiments further demonstrated H3K27me3 sites at the
promoter regions of CCL2, IL-34 and BMP7. Taken together, upregulated A3B suppressed occupancy of
H3K27me3 on the promoter of chemokines CCL2, IL-34 and BMP7 by inhibiting PRC2 activity.

In last decade, immunotherapy dramatically revolutionized the therapeutic landscape in oncology and was
announced as Breakthroughs of the Year by Science in 2013. However, the progress of introducing either
chimeric antigen receptor (CAR)-modified T cells or checkpoint inhibitors into HCC therapy is rather slow.
[11]
In 2017, Nivolumab was approved as the only anti-PD-1/L1 antibody for the treatment of HCC patients .
[12]
However, the response rate reached only about 20% . One major cause of such low effectiveness lies in
the immunosuppressive tumor microenvironment and immune escape. In addition to immunotherapy,
epigenetic therapy has drawn much attention in recent years as well. However, outcome of pre-clinical
and clinical trials of epigenetic drugs in HCC was rather disappointing, indicating other molecular
mechanisms involved in epigenetic modulation . This work by Wang and his colleagues discovered
[13]
a crucial role of A3B in promoting HCC initiation by modulating immunological microenvironment
via inhibition of H3K27 methylation, revealing A3B as a novel therapeutic target in immunotherapy of
HCC, explaining partially the current failure of epigenetic drugs, and demonstrating the significance of
combined therapy targeting both innate and acquired immune systems in future HCC treatment.

DECLARATIONS
Authors’ contributions
The author contributed solely to the article.

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
The author declared that there are no conflicts of interest.