Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 28, 2016; 22(28): 6469-6483
Published online Jul 28, 2016. doi: 10.3748/wjg.v22.i28.6469
Specific CD8+ T cell response immunotherapy for hepatocellular carcinoma and viral hepatitis
Elia Moreno-Cubero, Juan-Ramón Larrubia
Elia Moreno-Cubero, Juan-Ramón Larrubia, Translational Hepatology Unit, Guadalajara University Hospital, University of Alcalá, E-19002 Guadalajara, Spain
Elia Moreno-Cubero, Department of Biology of Systems, University of Alcalá, 28805 Alcalá de Henares (Madrid), Spain
Juan-Ramón Larrubia, Department of Medicine and Medical Specialties, University of Alcalá, 28805 Alcalá de Henares (Madrid), Spain
Author contributions: Moreno-Cubero E and Larrubia JR contributed equally to the conception and design of the review; Moreno-Cubero E wrote the manuscript; and Larrubia JR revised the final document.
Supported by “Instituto de Salud Carlos III”, Spain & “European Regional Development Fund (ERDF), a way of making Europe”, No. PI12/00130 and No. PI15/00074; “Gilead Spain & Instituto de Salud Carlos III”, No. GLD14_00217.
Conflict-of-interest statement: The authors declare that there are no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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:
Correspondence to: Juan-Ramón Larrubia, MD, MSc, PhD, Translational Hepatology Unit, Guadalajara University Hospital, University of Alcalá, E-19002 Guadalajara, Spain.
Telephone: +34-949-209200 Fax: +34-949-909256
Received: March 23, 2016
Peer-review started: March 24, 2016
First decision: May 12, 2016
Revised: May 21, 2016
Accepted: June 15, 2016
Article in press: June 15, 2016
Published online: July 28, 2016

Hepatocellular carcinoma (HCC), chronic hepatitis B (CHB) and chronic hepatitis C (CHC) are characterized by exhaustion of the specific CD8+ T cell response. This process involves enhancement of negative co-stimulatory molecules, such as programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), 2B4, Tim-3, CD160 and LAG-3, which is linked to intrahepatic overexpression of some of the cognate ligands, such as PD-L1, on antigen presenting cells and thereby favouring a tolerogenic environment. Therapies that disrupt these negative signalling mechanisms represent promising therapeutic tools with the potential to restore reactivity of the specific CD8+ T cell response. In this review we discuss the impressive in vitro and in vivo results that have been recently achieved in HCC, CHB and CHC by blocking these negative receptors with monoclonal antibodies against these immune checkpoint modulators. The article mainly focuses on the role of CTLA-4 and PD-1 blocking monoclonal antibodies, the first ones to have reached clinical practice. The humanized monoclonal antibodies against CTLA-4 (tremelimumab and ipilimumab) and PD-1 (nivolumab and pembrolizumab) have yielded good results in testing of HCC and chronic viral hepatitis patients. Trelimumab, in particular, has shown a significant increase in the time to progression in HCC, while nivolumab has shown a remarkable effect on hepatitis C viral load reduction. The research on the role of ipilimumab, nivolumab and pembrolizumab on HCC is currently underway.

Keywords: Hepatocellular carcinoma, CD8+ T cells, Immune checkpoint modulation, Chronic viral hepatitis, Cytotoxic T-lymphocyte antigen-4, Programmed cell death protein-1

Core tip: In certain types of chronic diseases, such as hepatocellular carcinoma and chronic viral hepatitis, disease curation involves restoration of the specific cytotoxic T cell response. Chronic hepatotropic viruses and tumoural cells develop mechanisms to induce exhaustion of the specific CD8+ T cells in order to escape immune destruction. One hallmark of this dysfunction is the overexpression of negative co-stimulatory molecules. Blockade of these negative co-stimulatory pathways, a process known as immune checkpoint modulation, is a promising novel therapy that could improve the treatment of liver diseases that feature T cell exhaustion.