Immune-based therapies for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related death. The immune-rich contexture of the HCC microenvironment makes this tumour an appealing target for immune-based therapies. Here, we discuss how the functional characteristics of the liver microenvironment can potentially be harnessed for the treatment of HCC. We will review the evidence supporting a therapeutic role for vaccines, cell-based therapies and immune-checkpoint inhibitors and discuss the potential for patient stratification in an attempt to overcome the series of failures that has characterised drug development in this disease area.

Fig. 1. The complex and multi-faceted functional interactions guiding cancer immune tolerogenesis in hepatocellular carcinoma.

Cellular and functional heterogeneity of the HCC tumour microenvironment.

Fig. 2. Principal functional networks driving NK cell function in hepatocellular carcinoma.

Key stimulatory and inhibitory interactions involved in NK cell/tumour cell recognition and killing.

Fig. 3. General overview of immune-based therapies for HCC.

a Simultaneous inhibition of CTLA-4 and the PD-1 axis by monoclonal antibodies (brown and blue respectively). The effect of dual checkpoint blockade on T-cell immune reconstitution is demonstrated, with CTLA-4 acting mainly on T-reg cells and antigen-presenting cells, and PD-1 acting on effector CD8+ CTLs. b Schematic representation of synergy between anti-angiogenic therapy (green antibody) and PD-1/PD-L1-targeted therapy. c Locoregional therapies, such as ablation and trans-arterial chemoembolisation are loco-regional inducers of immunogenic cell death and drive CD8+ cell infiltration into the tumour microenvironment, providing a rationale for combined anti-PD-1 therapy. d Autologous T cell transfer involves ex vivo activation of mixed T cell/NK cell populations by cytokines (i.e., CIK cells) and reinfusion into the patient with the intent of bypassing immune-evasion and eliciting an anti-tumour responses. e Anti-tumour vaccines against immunodominant peptides of oncofoetal proteins, such as AFP, GPC3 and hTERT, have been combined with ex vivo activation of dendritic cells to promote effective antigen presentation.