Immunotherapy against programmed death-1/programmed death ligand 1 in hepatocellular carcinoma: Importance of molecular variations, cellular heterogeneity, and cancer stem cells

Abstract

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy related to diverse etiological factors. Different oncogenic mechanisms and genetic variations lead to multiple HCC molecular classifications. Recently, an immune-based strategy using immune checkpoint inhibitors (ICIs) was presented in HCC therapy, especially with ICIs against the programmed death-1 (PD-1) and its ligand PD-L1. However, despite the success of anti-PD-1/PD-L1 in other cancers, a substantial proportion of HCC patients fail to respond. In this review, we gather current information on biomarkers of anti-PD-1/PD-L1 treatment and the contribution of HCC heterogeneity and hepatic cancer stem cells (CSCs). Genetic variations of PD-1 and PD-L1 are associated with chronic liver disease and progression to cancer. PD-L1 expression in tumoral tissues is differentially expressed in CSCs, particularly in those with a close association with the tumor microenvironment. This information will be beneficial for the selection of patients and the management of the ICIs against PD-1/PD-L1.

Keywords: Cancer heterogeneity; Cancer stem cells; Genetic variants; Hepatocellular carcinoma; Programmed death ligand 1; Programmed death-1.

Figure 1

Regulatory mechanism of programmed death-1/programmed death ligand 1 signaling in cancer. The interaction between programmed death-1 and programmed death ligand 1 (PD-L1) leads to the inhibition of T cell functional activation. PD-L1 expression in cancer cells is regulated by aberrant oncogenic pathways. PD-1: Programmed death-1; PD-L1: Programmed death ligand 1; TCR: T cell receptor; ITSM: Immunoreceptor tyrosine-based switch motif; ITIM: Immunoreceptor tyrosine-based inhibitory motif; IRF: Interferon regulatory factor.

Figure 2

The complexity of hepatocellular carcinoma and its microenvironment. A: Hepatocellular carcinoma and its tumor microenvironment are composed of various cell populations, including differentiated cancer cells, cancer stem cells, cancer associated fibroblasts, immune and endothelial cells; B: Programmed death-1 and programmed death ligand 1 interaction and inhibition by neutralizing antibodies in tumor growth. PD-1: Programmed death-1; PD-L1: Programmed death ligand 1; CSC: Cancer stem cells; CAF: Cancer associated fibroblast; ECM: Extracellular matrix; NK: Natural killer.