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B Cells Promote Liver Cancer With Dangerous Dual Strategy

Featured Publication, ZYTO,

Inflammatory fatty liver disease (NASH, nonalcoholic steatohepatitis) and the resulting liver cancer are driven by autoaggressive T cells. Scientists from the German Cancer Research Center (DKFZ), Helmholtz Munich and the Technical University Munich (TUM) now show what is behind this destructive behavior. In both mice and humans with NASH, they found increased numbers of activated B cells in the gastrointestinal tract. The B cells promote the development of liver cancer with a dual strategy: via direct cell-cell contact, they activate autoaggressive T cells. In addition, the B cells produce IgA class antibodies that activate specific immune cells, thereby driving liver fibrosis. When the B cells are turned off, inflammation and fibrosis regress in mice and there is no tumor development.

Liver cancer is the fourth leading cause of all cancer death worldwide according to the WHO. The disease is driven by chronic inflammation, that is triggered, for example, by viral infections or alcohol abuse. Very often, an unhealthy lifestyle is also the underlying cause: Too many calories, too little exercise and a too high body weight lead to a fatty liver. This, in turn, can result in non-alcoholic liver inflammation, also known as NASH, a veritable breeding ground for liver cancer.

Prof Mathias Heikenwälder and his team of scientists from the German Cancer Research Center recently found that NASH is driven by autoaggressive T cells that promote inflammatory tissue damage and even cancer development in the liver. Several experimental findings suggested that B cells producing IgA class antibodies play a role in this process. Heikenwälder's team investigated this suspicion in a recent study in mice. First author Valentina Leone from Helmholtz Munich contributed to the discovery of relevant genes and signaling pathways of immune cells involved in the disease by analyzing tissue samples and single cell sequencing.

The scientists discovered that in mice fed with a high-fat diet, inflammatory liver disease develops - much like in humans - and the animals often develop liver cell cancer. In contrast, mice that are genetically unable to produce B cells do not develop the disease under the same diet. In the livers of mice suffering from NASH, the researchers found a greatly increased number of activated B cells. In the small intestine, these B cells in turn activate metabolic T cells via direct cell-cell contacts. In addition, the immunoglobulin A (IgA) produced by the B cells activates another group of immune cells, macrophages, which carry special IgA receptors on their surface. The activated macrophages aggravate fibrotic changes in the liver. If the B cells are switched off with a specific antibody in the NASH-afflicted animals, both the inflammation driven by the autoreactive T cells and the fibrosis regress.

The team also examined tissue samples from people who had undergone surgery on the gastrointestinal tract to reduce weight ("bariatric surgery"). The findings strongly resembled those of mice suffering from NASH: Compared with healthy individuals, the tissue from NASH patients contained significantly more B cells, higher IgA levels and a higher number of activated macrophages.

"The results clearly show us that B cells as well as IgA are required to drive the pathological cascade in the development of liver cancer," Heikenwälder summarizes. "The good thing is that these results show us new ways to preventively interrupt this cancer-driving cascade: If we switch off the B cells with antibodies, the NASH symptoms regress and the animals develop fewer and smaller cancer foci. Fortunately, approved drugs already exist that suppress B-cell activation and that could possibly also stop NASH in humans and thus perhaps also liver cancer. However, there are no results from human studies on this yet."



About the scientists

Dr Valentina Leone, Postdoc at the Department of Gastroenterology at the Internal Medicine II of the Klinikum rechts der Isar at the technical University Munich (TUM)

PD Dr Kristian Unger, Lead Translational Bioinformatics, Research Unit Radiation Cytogenetics at Helmholtz Munich

Prof Dr Horst Zitzelsberger, Head of the Research Unit Radiation Cytogenetics at Helmholtz Munich

Original publication

Kotsiliti and Leone et al. (2023): Intestinal B cells license metabolic T-cell activation and contribute to fibrosis via IgA-FcR signalling in NASH. J Hepatology. DOI:


Kristian Unger

Prof. Dr. Kristian Unger

Cooperation AI-assisted therapy decisions in oncology, LMU University Clinics