Specific CD8⁺T cell response immunotherapy for hepatocellular carcinoma and viral hepatitis

Abstract

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.

Tim‐3 blockade promotes iNKT cell function to inhibit HBV replication

“…CHB is characterized by massive dysfunction of immune cells majorly including HBV‐specific CD8 + T cells and NK cells 31. One of the reasons leading to immune dysfunction is the expression of negative regulatory molecules, such as CTLA‐4, PD‐1 and IL‐10 32, 33. Tim‐3 is a newly identified molecule which has been reported playing important roles in regulating T cells, NK cells and macrophages.…”

“…31 One of the reasons leading to immune dysfunction is the expression of negative regulatory molecules, such as CTLA-4, PD-1 and IL-10. 32,33 Tim-3 is a newly identified molecule which has been reported playing important roles in regulating T cells, NK cells and macrophages. In some cases, like PD-1, Tim-3 was regarded as an exhaustion marker In our work, we detected increased membrane Tim-3 expression on iNKT cells in HBV-Tg mice.…”

Management of concomitant hepatocellular carcinoma and chronic hepatitis C: a review

“…Though markedly different pathological processes are involved in chronic hepatitis C and the development of HCC, there are some similarities between the two when considering the role of the immune system, with T cell exhaustion implicated in both [70] . CD8+ T cells are integral in targeting and destroying both tumour cells and cells infected with HCV.…”

“…T cell exhaustion exists to protect from tissue damage due to persistent and overzealous immunological response to antigens and is driven by upregulation of negative co-stimulatory pathways. With these pathways in action, key T cell effector processes are disrupted, they become tolerant of antigenic stimuli and ultimately apoptose [70] . T cell exhaustion is particularly efficient in T cells that are activated in the liver, causing the immunotolerant state required in an organ that encounters many antigenic threats.…”

4Mu Decreases CD47 Expression on Hepatic Cancer Stem Cells and Primes a Potent Antitumor T Cell Response Induced by Interleukin-12

“…23 TME is also an interesting target for anticancer immunotherapy, and this is of particular importance considering the promising results obtained on HCC by immune checkpoint inhibitors. [24][25][26] In addition to therapies that disrupt negative signaling mechanisms, immunotherapies destined to recruit immune effector cells into the tumors result in very attractive tools, 27 since tumor-infiltrating T cells have been found to be functionally compromised in patients with HCC. 28 The activation of effector immune cells is a key to mediate antitumor responses.…”