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Page 12 of 17 Shrestha et al. Hepatoma Res 2019;5:32 I http://dx.doi.org/10.20517/2394-5079.2019.24

studies demonstrating the direct link between EMT and immune checkpoint expression in HCC are
currently lacking.

A few studies have examined the regulation of immune checkpoints in HCC with cytokines that are known
to induce EMT, but no EMT markers were evaluated in these studies. One such study in HCC identified
that blocking PD-L1 and TGF-β enhanced the immune response against tumor suggesting the combination
[113]
approach of ICIs and TGF-β inhibitor drugs . The crosstalk between cytokines interferon (IFN)-γ and
[115]
[114]
TNF-α was shown to synergistically regulate PD-L1 expression in HCC cells . Brown et al. reported
that resistance to ICI therapy in HCC was dependent upon overexpression of an immune checkpoint
molecule, IDO-1. The authors demonstrated that IDO inhibitors could improve the efficacy and response
[115]
to ICI therapy . Although a few studies have explored the role of EMT in regulating immune checkpoints
in HCC, further studies are warranted in this area. A better understanding of how EMT confers resistance
to HCC cells treated with ICIs will enable us to develop more effective treatments for HCC.

Immunotherapy, in particular ICI therapy, has revolutionized the treatment approach in several cancers
including HCC. ICI treatment is the best alternative in advanced HCC where other curative treatments
are not applicable and when systemic therapies fail [20,25] . Several ICI clinical trials are underway for HCC,
the majority of them target PD-1, PD-L1 and CTLA-4 as monotherapy or in combination with other ICIs
[28]
or molecular targeted agents . Recent studies have identified several novel immune checkpoint molecules
that can be potential targets in HCC [25,116,117] .

Despite the clinical breakthrough of ICIs in HCC treatment, the response rate is unsatisfactory with a few
[28]
adverse effects . In addition, the resistance to ICI therapy has also limited the use of ICIs in a large patient
[72]
population . The challenge with ICI therapy is to increase the proportion of patients who may gain clinical
[38]
benefits from this therapy . The use of combination therapy with other ICIs may prove to be beneficial as
[72]
studies report the emergence of alternative checkpoint molecules reduce the response to ICI therapy . The
[118]
efficacy of ICI therapy can be improved by early identification and management of adverse events . The
selection of patient population who might respond to ICIs is another challenge of ICI therapy . Several
[119]
predictive biomarkers have been utilized such as expression of immune checkpoint molecules (PD-L1
expression by IHC) and TMB [25,120] . However, there are limitations to these biomarkers. Studies have shown
that PD-L1 negative patients also respond to anti-PD-1 and anti-PD-L1 treatments [120,121] . In addition, it has
been reported that patients with a lower number of mutations also benefited from ICI therapy along with
patients with higher mutational load [120,122] . Thus, there is an urgent need for better predictive biomarkers to
improve efficacy of ICI therapy.

Recent studies in several cancers have identified the role of EMT in regulation of immune checkpoint
expression. The association between EMT and immune checkpoint expression suggests the utility of EMT
status as a potential predictive biomarker in ICI therapy. In addition, EMT inhibitors in combination with
ICI may be a potential combination therapy to improve efficacy of ICI therapy in HCC. A few studies have
investigated the potential benefits of targeting both EMT and immune checkpoint molecules by utilizing
a fusion protein or antibodies targeting TGF-β and PD-L1 [101,123] . Drugs such as Silimarin and Apatinib
have been identified that could block both PD-L1 expression and EMT in non-small cell lung cancer and
osteoscaroma suggesting similar potential in HCC [114,124] . Collectively, inhibiting the EMT process could
increase the sensitivity to ICI treatments and both In vitro and in vivo HCC studies in this area will lay the
foundation for future clinical trials.

CONCLUSION
The emergence of ICIs has provided much hope in improved cancer therapy in several malignancies
including HCC. The majority of clinical studies for HCC are based on a few ICIs either as monotherapy or