Resident Immune Cells of the Liver in the Tumor Microenvironment

Abstract

The liver is a central immunomodulator that ensures a homeostatic balance between protection and immunotolerance. A hallmark of hepatocellular carcinoma (HCC) is the deregulation of this tightly controlled immunological network. Immune response in the liver involves a complex interplay between resident innate, innate, and adaptive immune cells. The immune response in the liver is modulated by its continuous exposure to toxic molecules and microorganisms that requires a degree of immune tolerance to protect normal tissue from damage. In HCC pathogenesis, immune cells must balance a dual role that includes the elimination of malignant cells, as well as the repair of damaged liver tissue to maintain homeostasis. Immune response in the innate and adaptive immune systems extends to the cross-talk and interaction involving immune-regulating non-hematopoietic cells, myeloid immune cells, and lymphoid immune cells. In this review, we discuss the different immune responses of resident immune cells in the tumor microenvironment. Current FDA-approved targeted therapies, including immunotherapy options, have produced modest results to date for the treatment of advanced HCC. Although immunotherapy therapy to date has demonstrated its potential efficacy, immune cell pathways need to be better understood. In this review article, we summarize the roles of specific resident immune cell subsets and their cross-talk subversion in HCC pathogenesis, with a view to identifying potential new biomarkers and therapy options.

Keywords: adaptive; cells; immunology; innate; liver; tumorigenesis.

Figure 1

Innate immune response in HCC-BM. In HCC pathogenesis, hepatic stellate cells (HSCs) drive fibrogenesis by promoting extracellular matrix (ECM), as well as directly influencing proliferation by expressing pro-inflammatory cytokines like interleukin-6 (IL-6) and hepatocyte growth factor (HGF). HSCs also express the glycoprotein CD44v3 that promotes cell migration and invasion in HCC. Natural killer T (NKT) cells also promote fibrogenesis while neutrophils express vascular endothelial growth factor (VEGF) to promote angiogenesis and proliferation. Neutrophils also activate monocytes that can both repress HCC by expressing interferon-gamma (IFN-γ) and promote HCC by expressing interleukin-10 (IL-10). Kupffer cells (KCs) also play a crucial role in HCC pathogenesis by promoting monocytes by expressing C-C motive chemokine ligand-2 (CCL2), which acts as a monocyte attracting protein. KCs also express damage-associated molecular pattern molecules (DAMPs) and are activated by HSC. Expression of histamine (HA) and epidermal growth factor (EGF), as well as HCC expression of reactive oxygen species (ROS) and hepatocyte growth factor (HGF). However, KC expression is modulated by myeloid-derived suppressor cells (MDSCs).

Figure 2

Adaptive immune response in HCC-BM. CD8⁺ T cells are considered the primary anti-cancer cells in HCC pathogenesis but their function is modulated by both the TME and the innate immune system. CD8⁺ T cells are modulated by regulatory T cells (T-reg cells) that express interleukin 10 (IL-10); T-reg cells can also promote the expression of transforming growth factor beta (TGF-B), which promotes HCC. Regulatory B cells (B-reg cells) can also directly promote HCC by expressing IL-10 or modulating CD8⁺ T-cell expression. HCC tumors can express programmed death ligand-1 (PD-L1) and galactin-9 (GAL-9) to repress CD8⁺ T cells that can also be repressed by liver sinusoidal endothelial cells (LSECs) that can express PD-L1 and dendritic cells (DCs) that express programmed cell death protein 1 (PD-1). Natural killer (NK) cells can repress both CD8⁺ T cells and HCC pathogenesis.