The role of steatotic liver disease in immune suppression and provision of a premetastatic niche

• Applicant: Dr. Dominic Denk
• Subject Area: Gastroenterology ; Immunology ; Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 548709808

The incidence of metabolic associated fatty liver disease (MAFLD) is growing exponentially and is a major risk factor for liver cirrhosis and primary liver cancer (hepatocellular carcinoma, HCC). Experimental data and clinical studies suggest that inflammatory progression from MAFLD to metabolic dysfunction-associated steatohepatitis (MASH) may increase the likelihood of other cancers (e.g. colorectal and pancreatic) metastasizing to the liver. In addition to being the key metabolic organ the liver is also an immune organ. All immune cells are strongly affected by their microenvironment, and lipids, which are secreted by hepatocytes, were shown to exert pro-tumorigenic and tolerogenic effects. Accumulation of neutrophils and conventional dendritic cells (cDCs), both functionally regulated by metabolic availability in the context of cancer, is a striking characteristic of human and murine MASH. Coincidentally, activated neutrophils and dysfunctional DCs are also key components of the so-called pre-metastatic niche that facilitates tumor metastasis. Whereas previous studies have focused on the effects of MASH on the liver immune system and its ability to control HCC growthm it is unknown how lipids secreted by steatotic hepatocytes affect the local immune system and its ability to either form a hospitable premetastatic niche or kill newly arriving metastatic seeds. We propose that neutrophils activated by lipid accumulation in MAFLD promote the formation of a pre-metastatic niche, whereas altered metabolism and mitochondrial dynamics polarize cDCs towards a tolerogenic state. Consequently, environmentally derived metabolic instruction of immune function hinders antitumor immunity and facilitates liver metastasis by pancreatic ductal adenocarcinoma (PDAC) and other cancers. Understanding these interactions is important for development of new treatments for liver metastatic cancers, which are invariably fatal, while also expaining environmental suppression of antitumor immunity.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Michael Karin, Ph.D.