Study reveals how B cells promote liver cancer with dangerous dual strategy
Heidelberg, Germany: Autoaggressive T cells cause inflammatory fatty liver disease (NASH, nonalcoholic steatohepatitis) and the ensuing liver cancer. Scientists from the German Cancer Research Centre (DKFZ) have finally discovered the cause of this harmful behaviour. They discovered an increase in the number of activated B lymphocytes in the gastrointestinal tract of both mice and humans with NASH. B cells promote the development of liver cancer by a twofold strategy: they stimulate autoaggressive T cells through direct cell-cell interaction. Furthermore, B cells create IgA class antibodies that stimulate particular immune cells, causing liver fibrosis. When B cells are switched off in mice, inflammation and fibrosis disappear, and fewer and smaller liver tumours form.
Liver cancer is the world's fourth largest cause of cancer mortality. Chronic inflammation, such as that caused by viral infections or alcohol addiction, drives the illness. A fatty liver is frequently caused by an unhealthy lifestyle: too many calories, too little activity, and a high body weight. This, in turn, can lead to non-alcoholic liver inflammation (NASH), a breeding ground for liver cancer.
"Worldwide, fatty liver and NASH are assuming pandemic proportions," says Mathias Heikenwalder of the German Cancer Research Center, a specialist in the links between chronic inflammation and liver cancer. Recently, a research team led by him found that NASH is driven by autoaggressive T cells that promote inflammatory tissue damage and even cancer development in the liver*.
What drives T cells to behave in this destructive manner? Several experimental findings suggested that B cells producing IgA class antibodies play a role in this process. Heikenwalder's team investigated this suspicion in a recent study in mice.
In mice fed 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.
The B cells exert their disastrous influence on the liver in two ways: In the small intestine, they instigate T cells to behave auto aggressively via direct cell-cell contacts. The researchers were also able to reproduce this in the culture dish when they brought B cells from NASH mice together with CD8 T cells from a healthy animal, which were thereby activated to autoaggressive behavior.
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.
Heikenwalder's 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," Mathias Heikenwalder 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."