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World J Stem Cells. Jul 26, 2021; 13(7): 795-824
Published online Jul 26, 2021. doi: 10.4252/wjsc.v13.i7.795
Immunotherapy against programmed death-1/programmed death ligand 1 in hepatocellular carcinoma: Importance of molecular variations, cellular heterogeneity, and cancer stem cells
Caecilia H C Sukowati, Korri Elvanita El-Khobar, Claudio Tiribelli
Caecilia H C Sukowati, Claudio Tiribelli, Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
Korri Elvanita El-Khobar, Hepatitis Unit, Eijkman Institute for Molecular Biology, Jakarta 10430, Indonesia
Author contributions: Sukowati CHC conceived the idea; Sukowati CHC and El-Khobar KE wrote the manuscript; Tiribelli C critically revised the text; all authors read and approved the manuscript.
Supported by 2020 Grant of the Fondazione Umberto Veronesi, Milan, Italy (to Sukowati CHC); and a Grant of the Regione Autonomo Friuli Venezia Giulia in Progetti Internazionali 2020 (DGR 2195 dd 20/12/2019) to the FIF.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Caecilia H C Sukowati, BSc, PhD, Senior Scientist, Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, AREA Science Park Basovizza, SS14 km 163.5, Trieste 34149, Italy. caecilia.sukowati@fegato.it
Received: February 18, 2021
Peer-review started: February 18, 2021
First decision: March 16, 2021
Revised: March 25, 2021
Accepted: May 7, 2021
Article in press: May 7, 2021
Published online: July 26, 2021
Processing time: 155 Days and 0 Hours
Abstract

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy related to diverse etiological factors. Different oncogenic mechanisms and genetic variations lead to multiple HCC molecular classifications. Recently, an immune-based strategy using immune checkpoint inhibitors (ICIs) was presented in HCC therapy, especially with ICIs against the programmed death-1 (PD-1) and its ligand PD-L1. However, despite the success of anti-PD-1/PD-L1 in other cancers, a substantial proportion of HCC patients fail to respond. In this review, we gather current information on biomarkers of anti-PD-1/PD-L1 treatment and the contribution of HCC heterogeneity and hepatic cancer stem cells (CSCs). Genetic variations of PD-1 and PD-L1 are associated with chronic liver disease and progression to cancer. PD-L1 expression in tumoral tissues is differentially expressed in CSCs, particularly in those with a close association with the tumor microenvironment. This information will be beneficial for the selection of patients and the management of the ICIs against PD-1/PD-L1.

Keywords: Hepatocellular carcinoma; Programmed death-1; Programmed death ligand 1; Cancer stem cells; Cancer heterogeneity; Genetic variants

Core Tip: Immune checkpoint inhibitors (ICIs), in particular the ICIs against the programmed death-1/programmed death ligand 1 (PD-L1/PD-L1) axis, have recently been presented for the treatment of hepatocellular carcinoma (HCC). However, despite the success of anti-PD-1/PD-L1 in other cancers, a substantial proportion of HCC patients fail to respond. Here, we gather current information on biomarkers of anti-PD-1/PD-L1 treatment and the contribution of HCC heterogeneity and hepatic cancer stem cells.