Immune suppressive checkpoint interactions in the tumour microenvironment of primary liver cancers

Abstract

Liver cancer is one of the most prevalent cancers, and the third most common cause of cancer-related mortality worldwide. The therapeutic options for the main types of primary liver cancer-hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA)-are very limited. HCC and CCA are immunogenic cancers, but effective immune-mediated tumour control is prevented by their immunosuppressive tumour microenvironment. Despite the critical involvement of key co-inhibitory immune checkpoint interactions in immunosuppression in liver cancer, only a minority of patients with HCC respond to monotherapy using approved checkpoint inhibitor antibodies. To develop effective (combinatorial) therapeutic immune checkpoint strategies for liver cancer, in-depth knowledge of the different mechanisms that contribute to intratumoral immunosuppression is needed. Here, we review the co-inhibitory pathways that are known to suppress intratumoral T cells in HCC and CCA. We provide a detailed description of insights from preclinical studies in cellular crosstalk within the tumour microenvironment that results in interactions between co-inhibitory receptors on different T-cell subsets and their ligands on other cell types, including tumour cells. We suggest alternative immune checkpoints as promising targets, and draw attention to the possibility of combined targeting of co-inhibitory and co-stimulatory pathways to abrogate immunosuppression.

Fig. 1. Co-inhibitory ligand–receptor interactions in liver cancer.

a Potential interactions between co-inhibitory receptors on T cells and their corresponding ligands on tumour cells or antigen-presenting cells (dendritic cells, macrophages/monocytes) in HCC or CCA. b Expression of co-inhibitory ligands on diverse cell types and expression of co-inhibitory receptors on different T cells in HCC or CCA tumours, according to the data currently available.

Fig. 2. Mechanisms by which co-inhibitory immune checkpoint interactions suppress T cells.

Several mechanisms of immune-suppressive function can be mediated by co-inhibitory receptor-ligand interactions. (i) Upon binding by their corresponding ligand, co-inhibitory receptors can deliver suppressive signals within the T cells on which they are expressed; these signals suppress activatory receptor signalling (e.g. by the T-cell-receptor (TCR) or CD28). (ii) Co-inhibitory receptor binding can deliver suppressive signals to the ligand-expressing cells (e.g. PD-1 binding to PD-L1 induces functional changes in antigen-presenting cells). (iii) Co-inhibitory receptors can compete with co-stimulatory receptors for the same ligand (e.g. CTLA4 and CD28 compete for CD80 and CD86, TIGIT and CD226 compete for CD155). (iv) Co-inhibitory receptors can block homodimerization of co-stimulatory receptors, thereby preventing the co-stimulatory signal from being generated (TIGIT physically prevents CD226 from signaling). Purple arrows indicate stimulatory signals, red arrows indicate inhibitory signals.