Immune Checkpoint Therapy in HBV

HBV infection is a worldwide public health concern, and chronic HBV infection is one of the high-risk factors for human hepatocellular carcinoma (HCC). Approximately 257 million people worldwide are chronically infected with HBV, and about 900,000 people annually die from HBV-related liver failure or HCC. Many studies have reported that immune checkpoint molecules play important roles in HBV infections by inhibiting the activation of the immune system and removing HBV infected cells. Therefore, immune checkpoint proteins are promising therapeutic targets, and immunotherapy with immune checkpoint inhibitors (ICIs) is a potent treatment for HBV infections.

Immune Checkpoint Proteins and HBV Infections

HBV-specific T cells expressing multiple immune checkpoint proteins have been shown to play a crucial role in HBV infection progress. In untreated chronic HBV infection, high levels of PD-1, CTLA-4, and TIM-3 are expressed on total and HBV-specific CD8⁺ T cells. In acute HBV infection, high levels of PD-1 are present on circulating and intrahepatic CD8⁺ T cells, which inhibit intrahepatic inflammation. High levels of PD-L1, the ligand for PD-1, are also found on circulating CD14⁺ monocytes, and CD19+ B cells in chronic HBV infection, liver cirrhosis, and HCC be responsible for ongoing T cell exhaustion. Besides, high levels of PD-1 are also expressed on HBV-specific CD4⁺ T cells, but the levels of CTLA-4, TIM-3, KLRG1, or 2B4 are not increased.

Furthermore, scientists also characterized the phenotype of intrahepatic CD4⁺ and CD8⁺ T cells in HBV infection. High infiltration of total and HBV-specific intrahepatic CD8⁺ T cells was found in chronic HBV infection. The increased expression of PD-1 and TIM-3 was also found on intrahepatic T cells. Kupffer cells expressing high levels of galectin 9, the ligand of TIM-3, have been shown to exhibit a role in persisting intrahepatic T cell exhaustion. In addition, there have been identified some intrahepatic CD8⁺ T cells expressing other proteins of exhaustion (such as BTLA) which may suppress the function of effective T cells by producing IL-10.

Fig.1 Immune checkpoints in HIV and HBV infection. (Wykes, 2018)

Immune Checkpoint Therapy in HBV Infections

Immune checkpoint blockade, used either alone or in combination, has been proved as an effective therapeutic strategy for HBV infection through boosting T cell functions, even potentially increasing the production of antibodies against HBsAg. Most ex vivo studies have reported that inhibition of PD-1, CTLA-4, 2B4, and TIM-3 can increase HBV-specific CD8⁺ T cell function, relieving HBV infections in individuals with chronic HBV infection. Besides, some studies also reported that blocking PD-1 but no other inhibitory proteins partially improved the function of HBV-specific CD4⁺ T cells, with increased the production of IFNγ, IL-2, and tumor necrosis factor (TNF).

Moreover, in vivo studies also show checkpoint blockade could improve the function of HBV-specific T cells. For example, blockade antibodies such as anti-PD-L1 and anti-PD-L2 antibodies partially restore T cell function without hepatotoxicity in woodchuck hepatitis virus (WHV)-infected animals. However, there may be several theoretical risks in the treatment of HBV infection with checkpoint blockade, such as increased infiltration of reactivated T cells into the liver, which may trigger inflammation. Hence, extensive works are still needed to validate the effect of immune checkpoint blockade for treating HBV infections.

Services at Creative Biolabs

Creative Biolabs is a well-recognized service provider who supports a broad range of immune checkpoint therapy development for worldwide clients, including custom antibody, protein, peptide, and small molecule drug development of immune checkpoints. We also provide in vivo and in vitro assay services to assess the effect of immune checkpoint therapy. Our excellent in-home scientists are working with you to design an optimal solution to facilitate your success. Please do not hesitate to contact us for more detailed information.

Reference

1. Wykes, M.N.; et al. Immune checkpoint blockade in infectious diseases. Nature Reviews Immunology. 2018, 18: 91-104.

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