The immune landscape of hepatocellular carcinoma-where we are?

Abstract

Hepatocellular carcinoma (HCC) is one of the most common types of cancer diagnosed worldwide. After a decade of stagnation, several novel compounds have recently been shown to be effective in the treatment of HCC. Since immunotherapy is associated with important clinical benefits in some, but not all patients, it is essential to identify reliable predictive biomarkers. As the complex interplay between hepatocytes and immune cells is highly dependent on the tumor microenvironment, the tumor microenviroment has been suggested to be an important factor associated with the response to therapy and is currently being extensively investigated. Within this network, several important factors should be highlighted. Most of the cells are hepatocytes, but fibroblasts, endothelial cells, and immune cells are also present. Tumor-infiltrating leukocytes include several populations of cells and each of them plays a role in forming the tumor environment. Some of these cells may have antitumor effects, whereas others may be associated with the progression of the disease. The most important subsets include tumor-associated macrophages, tumor-associated neutrophils, and lymphocytes. These groups are described in the present review. The immune response is controlled by immune checkpoint molecules. One of the most important molecules involved in this checkpoint process seems to be the programmed death-1 (PD-1) receptor, which typically is induced on activated T cells, natural killer (NK) cells, B cells, and antigen-presenting cells. On the other hand, programmed death ligand 1 (PD-L1) is expressed by tumor cells, hepatocytes and hepatic stellate cells, and Kupffer cells or liver sinusoidal cells. Complex interactions between ligands and receptors are dependent on the signals from the microenvironment leading to either cancer development or apoptosis. Evidence from several studies indicates that patients with higher expression levels of PD-L1 on tumor cells or immune cells are more likely to achieve beneficial results from treatment with checkpoint blockers. This review focuses on the basic information regarding the microenvironment and its components, particularly on immune system involvement.

Keywords: hepatocellular carcinoma; immunotherapy; tumour microenvironment; tumour-associated macrophages; tumour-infiltrating lymphocytes.

Figure 1.

Anti-VEGF and anti-PD-1/PD-L1 treatment: Mechanism of action. PD, programmed death; PD-L1, programmed death-ligand 1; VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2.

Figure 2.

Potential factors involved in response to immunotherapy. mi-RNA, microRNA; NASH, non-alcoholic steatohepatitis; PD-1/PD-L1, programmed death 1/programmed death ligand 1; TMB, tumor mutational burden.