Journal
WORLD JOURNAL OF GASTROENTEROLOGY
Volume 22, Issue 28, Pages 6469-6483Publisher
BAISHIDENG PUBLISHING GROUP INC
DOI: 10.3748/wjg.v22.i28.6469
Keywords
Hepatocellular carcinoma; CD8(+) T cells; Immune checkpoint modulation; Chronic viral hepatitis; Cytotoxic T-lymphocyte antigen-4; Programmed cell death protein-1
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Funding
- Instituto de Salud Carlos III, Spain
- European Regional Development Fund (ERDF), a way of making Europe [PI12/00130, PI15/00074]
- Gilead Spain & Instituto de Salud Carlos III [GLD14_00217]
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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 costimulatory 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.
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