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inhibitors . Of note, current clinical trials are focusing on how immunosuppressive conditions in HCC
[83]
might be overcome using immune checkpoint inhibitors in combination with different types of immune
checkpoint blockades, TKIs, and other conventional treatments . To improve the HCC immunotherapy
[83]
strategies as well as immune stimulatory approaches, identification of TAAs and neoantigens specific to
HCC and testing the potential benefits of combinatorial immunotherapies will achieve the most beneficial
effect for HCC patients .
[59]

CONCLUSIONS AND FUTURE PERSPECTIVES
The journal Science selected cancer immunotherapy as its “Breakthrough of the Year” in 2013, and especially
the use of immune checkpoint blockade in cancer therapy is making a paradigm shift in cancer treatment [20,95] .
Of note, immunotherapy has the potential to achieve complete, long-lasting remissions and cancer cures,
representing the most promising new cancer treatment approach with few side effects . Although disease
[74]
progression is sometimes observed immediately after initiation of immunotherapy, some responders
require longer duration of immunotherapy to achieve tumor response . Therefore, the biomarkers of
[20]
immunotherapy to predict response are urgently needed, both from the perspective of the effective use
of medical resources and to prevent adverse effects caused by unnecessary treatment . There are several
[84]
highly promising candidate predictors of the cancer immunotherapy: PD-L1 expression in tumor tissue,
TAA related mutanome analyses including next-generation sequencing, and the immunome analyses, which
employ T cell repertoire analysis and proteomic analysis . Also, additional questions still remain regarding
[96]
the most effective combination of therapeutic modalities and biomarkers to predict long term treatment
outcomes in HCC immuno-oncology.

Notably, to date, very promising published evidence with checkpoint inhibitors in HCC has been reported
in the clinical trials of anti-CTLA-4 agent tremelimumab and a large phase II trial with anti-PD-1
agent nivolumab [56,78,80] . Further investigations of immuno-oncology potentially spread the applications
of immunotherapy in the various stages of HCCs, and thus immune-based therapies will bring about a
paradigm shift of anti-cancer treatment for HCC. We hope the immunotherapy will play a key role in HCC
treatment in the near future.

DECLARATIONS
Authors’ contributions
Made substantial contributions to conception and design of the study and performed data analysis and
interpretation: Lee JH, Nishida N
Performed data acquisition, as well as provided administrative, technical, and material support: Oh SY, Kim JY

Availability of data and materials
Not applicable.

Financial support and sponsorship
This study was supported by a grant of the Korea Healthcare technology R&D project, Ministry for Health,
Welfare & Family Affairs, Republic of Korea (HI13C1398).

Conflicts of interest
The authors declare there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.