The Role Of Myeloid Derived Cells In The Progression Of Liver Disease

Cells of the myeloid lineage display diverse roles and functions both in tissue homeostatic conditions and during the development of liver diseases. Hepatic myeloid cells such asKupffer cells exert immune surveillance while maintaining immune tolerance. This helps to prevent excessive immune stimulation upon encounter with gut-derived antigens from food and commensal microbes, or rapidly identifying and eliminating pathogens. Myeloid cells also exhibit a dual role by contributing to both the initiation and progression of liver diseases. During liver inflammation, myeloid cells secrete cytokines and chemokines that promote chemotaxis and tissue damage. Further down the process they can undergo reprogramming into pro-resolving, anti-inflammatory cells. In extremis, these can lead to loss of liver function and development of fibrosis and cirrhosis. Liver myeloid cells can also dictate the progress of hepatic malignancy by either promoting the infiltration and activation or suppressing the activities of effector and/or cytotoxic T cells.

Chronic hepatitis B (CHB) is a life-threatening liver disease affecting 257 million people worldwide, in particular in the Asia-Pacific regions. In endemic areas, hepatitis B virus (HBV) is usually transmitted from chronically infected mothers to neonates. Perinatal HBV infection causes chronic infection in more than 90% of exposed individuals. With perinatal infection, lifetime mortality risk due to complications of liver cirrhosis (LC) or hepatocellular carcinoma (HCC) reaches up to 40% in men and 15% in women. For the treatment of chronic HBV infection, nucleos(t)ide analogue antivirals have been successfully used to suppress viral replication. However, HBV exists as a cccDNA, which cannot be eliminated by nucleos(t)ide analogues. Therefore, a practical goal of novel HBV therapeutics can be HBs seroconversion (loss of HBsAg and development of HBsAg-specific antibodies), which occurs during spontaneous recovery from acute HBV infection. This HBs seroconversion is referred to as “functional cure” of HBV infection. When functional cure is reached, HBsAg-specific antibodies have virus-neutralizing activity and control HBV infection even in the presence of cccDNA. Currently, peg-IFN-a is often used to induce HBs seroconversion in patients with chronic HBV infection; however, the efficacy is not satisfactory. In future, other immunological therapeutics must be considered to achieve HBs seroconversion, including therapeutic vaccines and immune checkpoint blockers.

Myelomonocytes are the multipotent cells in the stage of blood cell differentiation, which mainly comprise blood monocytes, tissue macrophages and subset of dendritic cells. Actually, their position and ability of judgement of the health of tissue or organ environment are the key initiators of tissue-specific immune response in a local and global fashion. Interestingly, the morpho-functional aspects of this group of cells vary to a wide range with their positional diversity. Their ability to communicate or represent the tissue microenvironment to the peripheral immune system and efficiency to engage the system to effector activation hold the key for a successful immune endeavour. The present volume shows some glimpses of such an extensive area of current immunology research.

In this book we provide insights into liver – cancer and immunology. Experts in the field provide an overview over fundamental immunological questions in liver cancer and tumorimmunology, which form the base for immune based approaches in HCC, which gain increasing interest in the community due to first promising results obtained in early clinical trials. Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death in the United States. Treatment options are limited. Viral hepatitis is one of the major risk factors for HCC, which represents a typical “inflammation-induced” cancer. Immune-based treatment approaches have revolutionized oncology in recent years. Various treatment strategies have received FDA approval including dendritic cell vaccination, for prostate cancer as well as immune checkpoint inhibition targeting the CTLA4 or the PD1/PDL1 axis in melanoma, lung, and kidney cancer. Additionally, cell based therapies (adoptive T cell therapy, CAR T cells and TCR transduced T cells) have demonstrated significant efficacy in patients with B cell malignancies and melanoma. Immune checkpoint inhibitors in particular have generated enormous excitement across the entire field of oncology, providing a significant benefit to a minority of patients.