T cells in the heterogeneous tumour immune microenvironment of hepatocellular carcinoma: Implications for immune checkpoint inhibitor therapy

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Recently, patient care was revolutionized by the introduction of immunotherapy combining anti-programmed death-ligand 1 (PD-L1) checkpoint inhibition with anti-vascular endothelial growth factor (VEGF) therapy as first-line treatment for advanced unresectable HCC. Additional promising studies with mono- or combination immunotherapy are in advanced phases of clinical testing. Currently, however, our understanding of which patients profit from immunotherapy and how therapy response may be related to the composition of the tumour immune microenvironment remains incomplete. Inhibitory receptors as targets of immune checkpoint inhibitor (ICI) therapies are strongly expressed by T cells in the tumour microenvironment (TME). However, the HCC microenvironment is highly heterogeneous as illustrated by distinct molecular subtypes and subclassifications with an immune-rich microenvironment representing only a small proportion of HCCs. A better understanding of the tumour immune microenvironment is expected to provide insights for clinically applicable biomarkers to optimize immunotherapies. Recent studies identified subtypes of PD-1 expressing CD8+ T cells with divergent function in the HCC TME associated with different outcomes, suggesting that specific PD-1 expressing CD8+ tissue-resident memory T cells (TRM), but not exhausted CD8+ T cells (TEX), govern positive therapy outcomes. This review discusses the T-cell response in the HCC TME in the context of its heterogeneity, molecular and immune classifications and implications for ICI therapy and biomarker discovery.