HBV-Induced Immune Imbalance in the Development of HCC

Abstract

Chronic hepatitis B virus (HBV) infection is one of the high-risk factors for human HCC. Despite the integration of virus DNA and the oncoprotein HBx, chronic necroinflammation and hepatocellular regeneration account for hepatocarcinogenesis. As a non-cytopathic virus, HBV is extensively recognized to mediate chronic liver damage through abnormal immune attack. However, the mechanisms driving HBV infection to HCC are poorly understood. During chronic HBV infection in humans, the adaptive immunity changes from immune tolerance to progressive immune activation, inactivation, reactivation and exhaustion, all of which may be the immune pathogenic factors for the development of HCC. Recently, the immunopathogenic mechanisms were described in mouse HBV-induced HCC models, which is absolutely dependent on the presence of HBV-specific T cell response and NK cell-derived IFN-γ, findings which are consistent with the observations from CHB and HCC patients. In this review, we summarize recent research progression on the HBV-specific CD8⁺ T cells, and also CD4⁺ T cells, B cells and non-specific immune cells and molecules underlying chronic HBV infection and eventual HCC development to demonstrate the pathogenesis of HBV-induced immune imbalance. Based on the progression, we discussed the potential of immune-based therapies and their challenges in the treatment of HBV-related HCC, including the checkpoint inhibition, genetically modified T cell transfer, therapeutic vaccines and metabolic modulation.

Keywords: HBV; HCC; adaptive immunity; immune dysfunction; innate immunity.

Figure 1

HBV infection relates to the magnitude and quantity of anti-viral immune response. (A) Self-limited acute HBV infection. NK cells and NKT cells play important roles in early control of HBV, and then a robust response of CD4⁺ T cells and CD8⁺ T cells is generated to control and eliminate HBV. B cells co-stimulated by T cells produce anti-HBs, anti-HBe and anti-HBc. These protective antibodies clear HBV antigens and virus from the circulation, and prevent or limit HBV reinfection. (B) Chronic HBV infection. Five stages are identified including “immune tolerant” stage with a high-replication of HBV-DNA and low-inflammation, “immune active” stage with HBV-specific CD8⁺ T cell response and antibody production which results in chronic liver injuries, inflammations and liver regeneration, “immune inactive” stage with low-replication of HBV and limited inflammation, “immune reactive” stage with chronic hepatitis progressed to liver fibrosis, cirrhosis and HCC, and in the late stage of “immune exhaustion.”

Figure 2

CD8⁺ T cell response in HBV-related HCC. In the HBV-infected individuals, there are several kinds of CD8⁺ T cell populations including exhausted HBV-specific CD8⁺ T cells, HBV core-specific and polymerase-specific CD8⁺ T cells with long-term memory-like phenotype, effector CD8⁺ T cells and HBV non-specific CD8⁺ T cells. The function of each CD8⁺ T cell population is different but possibly promote the development of HCC together. Additionally, regulatory CD4⁺ T cells (Tregs) also play a critical role in the stage of HCC for immune escape, for example inducing CD8⁺ T cell exhaustion.

Figure 3

Cross-talk among immune cells in the development of HBV-related HCC. During chronic HBV infection, there are complicate interactions among immune cells. Activation of CD8⁺ T cells is enhanced by CD4⁺ T and monocytes; and then activated CD8⁺ T cells recruit and activate macrophages. Activation of NKT cells can be promoted by Kupffer cells, and further activate NK cells and HSCs. On the other hand, suppressive Tregs, Kupffer cells and Bregs inhibit the activation of CD4⁺ T, CD8⁺ T, and NK cells. Furthermore, Tregs, Kupffer cells, and MDSCs contribute to the formation of exhausted CD8⁺ T and NK cells. A variety of cytokines including IFN-γ, TNF-α, IL-6, MCP-1, IL-4, IL-13, IL-12, IL-17, IL-10, and TGF-β are involved in the cross-talk between immune cells. Additionally, complement protein such as C5a positive regulate the activation of HSCs.