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Page 2 of 17 Shrestha et al. Hepatoma Res 2019;5:32 I http://dx.doi.org/10.20517/2394-5079.2019.24

Keywords: Hepatocellular carcinoma, immunotherapy, immune checkpoint inhibitors, epithelial-to-mesenchymal
transition, programmed cell death protein-1, programmed death-ligand 1, resistance

INTRODUCTION
Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and is associated
[1]
with a high mortality rate . The incidence of HCC is increasing annually by 3%-9% worldwide and the
[2]
number of new cases and the number of deaths are almost in equal proportions . Patients diagnosed
with early stage HCC, have a better prognosis than advanced stage HCC patients with unresectable
[3]
tumors . Surgical resection and liver transplantation, the curative treatment approaches for early stage
[4,5]
HCC provides 5-year survival rate of greater than 70% . Loco-regional therapies such as radiofrequency
ablation (RFA), thermal and non-thermal ablation and transarterial chemoembolization (TACE) are also
[6-8]
available as alternative treatment options for unresectable early stage HCCs . However, the multi-targeted
tyrosine kinase inhibitor (TKI) Sorafenib and Lenvatinib are the only first-line treatment available for the
[9]
inoperable advanced stages of HCC .
[10]
As the survival benefit with Sorafenib is limited to only 3 months , several clinical trials have
[11]
examined the suitability of new drugs for the treatment of patients with advanced stage HCC . TKIs
such as Regorafenib, Ramucirab, and Cabozanitib have been recently approved by the Food and Drug
Administration (FDA) as second-line treatment alternatives for HCC patients previously treated with
Sorafenib [12-15] . In addition, a combination therapy of TACE plus Sorafenib from the TCTICS trial also
[11]
reported improved progression-free survival . However, the limited survival benefit and associated
toxicity with TKIs suggests an urgent need for better and efficacious treatment approaches for advanced
stage HCC.

Immunotherapy has emerged as a potential alternative in the treatment of cancers following the clinical
success of immune checkpoint inhibitors (ICIs). ICIs target the negative immune regulatory pathways
such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and the programmed cell death protein-1/
programmed cell death ligand 1 (PD-1/PD-L1) which inhibit T-cell immune response. ICI treatments
have demonstrated dramatic anti-tumor clinical effects in several malignancies including melanoma, lung
cancer and renal cell carcinoma [16-19] . Immunotherapeutic approaches based on ICIs have substantially
enhanced disease-free survival in HCC patients resulting in the approval of anti PD-1 monoclonal
antibodies, Nivolumab and Pembrolizumab, as second-line treatment options for advanced HCC [20-22] .
Notably, Nivolumab increases survival in HCC patients to 17 months, far exceeding the 3 months extension
[20]
in survival offered by Sorafenib .
In this review, we will highlight the clinical trials that address the utility of ICIs as therapeutic tools in
the management of HCC. We will focus on ICIs as monotherapies and combination therapy regimen for
HCC patients. Although ICIs have proven to be effective, therapeutic resistance occurs in the majority
of patients, leading to tumor progression. We explore EMT process as a main resistance mechanism to
immune checkpoint blockade therapy and review studies that link EMT to immune checkpoint regulation.

IMMUNOTHERAPY BASED ON IMMUNE CHECKPOINT BLOCKADE
Immune equilibrium is vital for preventing uncontrolled immune responses leading to severe inflammatory
conditions or autoimmune disorders [23,24] . The immune equilibrium is maintained by balance between co-
inhibitory and co-stimulatory signals that regulate T-cell activation [23-25] . T-cells are activated when specific
antigens are recognized by T-cell receptors, whereas, the immune checkpoints provide an inhibitory effect
on the activation of T-cells [23,24] . Immune checkpoint molecules are thus responsible for self-tolerance and