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Shrestha et al. Hepatoma Res 2019;5:32 Hepatoma Research
DOI: 10.20517/2394-5079.2019.24

Review Open Access

Immune checkpoint blockade therapies for HCC:
current status and future implications

Ritu Shrestha , Kim R. Bridle , Darrell H. G. Crawford , Aparna Jayachandran 1,2
1,2
1,2
1,2
1 The University of Queensland, Faculty of Medicine, Brisbane, Queensland 4120, Australia.
2 Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, Queensland 4120, Australia.
Correspondence to: Dr. Aparna Jayachandran, The University of Queensland, Faculty of Medicine, Lower Lobby Level,
Administration Building, Greenslopes Private Hospital, Greenslopes, Queensland 4120, Australia.
E-mail: a.jayachandran@uq.edu.au
How to cite this article: Shrestha R, Bridle KR, Crawford DHG, Jayachandran A. Immune checkpoint blockade therapies for HCC:
current status and future implications. Hepatoma Res 2019;5:32. http://dx.doi.org/10.20517/2394-5079.2019.24
Received: 27 Jun 2019 First Decision: 11 Jul 2019 Revised: 6 Aug 2019 Accepted: 9 Aug 2019 Published: 3 Sep 2019

Science Editors: Jia Fan, Ying-Hong Shi Copy Editor: Jia-Jia Meng Production Editor: Jing Yu

Abstract
Received: First Decision: Revised: Accepted: Published:
Hepatocellular carcinoma (HCC) is the most lethal and common type of liver cancer with limited treatment options
Science Editor: Copy Editor: Production Editor: Jing Yu at the advanced stage. The use of immune checkpoint inhibitor (ICI) based immunotherapy is exponentially
increasing in the treatment of patients with advanced solid tumors. The expression of immune checkpoints on
tumor cells leading to lower activity of T-cells is one of the major mechanisms of immune escape. Checkpoint
blockade immunotherapies with antibodies against PD-1, PD-L1 or CTLA-4 are being investigated in clinical trials
in HCC patients. ICIs have improved survival in patients with inoperable advanced stage HCC where other curative
treatments are not applicable. However, the response rates remain low with only a small subset of patients responding
to this therapy. There is an unmet need to identify predictive markers to select those HCC patients who would
benefit from ICI therapies. Importantly, epithelial-to-mesenchymal transition (EMT), a major process driving HCC
invasion and metastasis by regulating the phenotypic cellular switching from epithelial to mesenchymal state, has
been implicated as a resistance mechanism associated with ICI therapies. The role of EMT as a regulator of immune
checkpoint molecule in HCC is just emerging. However, the consequence of EMT as a resistance mechanism in HCC
patients undergoing ICI treatments remains unexplored. In this review, we summarize the recent clinical studies with
ICIs in HCC and highlight the trials underway featuring novel monotherapies and combinatorial approaches based
on immune and non-immune therapies. We will discuss the ongoing efforts to discover new immune checkpoint
molecules in HCC as potential drug targets. We also highlight the role of EMT in facilitating therapy resistance in
HCC treated with ICIs and discuss potential strategies to circumvent resistance in ICI treated HCC patients.

© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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