Newly discovered process revs up immune cells

Cancer cells use an unusual mechanism to invade new tissue and form metastases there. The same process probably also keeps some immune cells on their toes. This is the result of a current study led by the University of Bonn.

According to the study, certain structures called centrioles increase in number. This makes it easier for them to maintain their direction and thus travel more quickly to the lymph nodes, where they activate other immune cells. The results have now been published in Journal of Cell Biology.

Like the police, the immune system also depends on the division of labour. First, there are the dendritic cells. They search the tissue around the clock for traces of suspicious intruders, so-called antigens. If successful, they rush to the lymphatic vessels and from there to the draining lymph nodes. There they present their findings to a powerful search team, the T-cells. These endogenous troops now know which enemy they must fight.

This attack must take place before the invaders do much damage or multiply too much. It is therefore important that dendritic cells migrate to the lymph nodes as quickly as possible. “We have discovered a mechanism that helps them,” explains Prof. Dr. Eva Kiermaier from the LIMES Institute (Life and Medical Sciences) at the University of Bonn. “To do this, they increasingly form certain structures, so-called centrosomes. These help them to maintain their direction longer and thus reach the lymphatic vessels faster.”

Important function in cell division

Centrosomes belong to the organelles – these are molecular complexes that are responsible for specific tasks in cells, similar to the organs in the body. Normally there is exactly one centrosome in every human cell. It doubles just before cell division. The two copies migrate to opposite poles of the cell and span a bundle of fibers between them, the microtubules.

They use them to pull the chromosomes (which have also doubled) apart during division. Each of the resulting daughter cells thus receives a complete genome and one of the two centrosomes.

“Centrosomes are also responsible for organizing the cytoskeleton during cell migration,” says Kiermaier, who was brought to the Rhine from Lower Austria (IST Austria, Klosterneuburg) in 2017 via the returnee program of the state of North Rhine-Westphalia. “By that we mean fibrous structural proteins that give the cell its shape and stability.”

The cytoskeleton also decides where “front” and “back” are in a cell. And that, in turn, affects its direction of movement. “We have now been able to show that dendritic cells form several centrosomes as soon as they come into contact with an antigen,” says Ann-Kathrin Weier. The Ph.D. Student at the LIMES Institute shares the lead authorship of the publication with her colleague Mirka Homrich. Both performed important parts of the experiments.

Stay on course longer to reach your destination faster

Dendritic cells have a problem: They don’t know where the next lymphatic vessel is through which they can reach the lymph node. They use a “trial and error” strategy in their search: they run briefly in one direction and then change direction if they don’t encounter a ship.

“The more centrosomes they have, the longer they stay on course before continuing their search in another direction,” says Mirka Homrich. “We were able to show in computer simulations that this allows them to find the lymphatic vessels much faster than usual.” The proliferation of the centrosomes adjusts their stamina just right – so that they don’t stick to their direction too stubbornly. This would increase the risk of them getting lost and being lost entirely.

The mechanism identified in the study was previously completely unknown in healthy cells. It has been thought that cancer cells use it to form metastases. However, the multiplied centrosomes must not be freely distributed in the cells. Otherwise, they would severely disrupt functions such as cell division. In both tumor and dendritic cells, the organelles therefore congregate in a single place – they accumulate.

“There are now drugs that disrupt this accumulation of centrosomes,” says Kiermaier, who is also a member of the Cluster of Excellence ImmunoSensation2 and the transdisciplinary research area “Life and Health” at the University of Bonn. “As a result, the cancer cells can no longer divide properly and instead die.”

However, it is also possible that these substances interfere with the immune system – after all, the centrosomes also accumulate there. “We tested several of these active ingredients in cell cultures,” she says. “We actually found indications that they could significantly impair the effectiveness of the immune system.” If this were to be confirmed in clinical studies, that would be bad news, since the use of the active ingredients in cancer therapy could lead to significant side effects.