Putting the immune system on its feet

7 July 2025

Anyone who thinks our immune cells are smooth, round little balls is mistaken. Hundreds of tiny feet are dynamically extended and retracted from these cells to gently "kick" their surroundings. If they bump into something hard, it can have major consequences, say cell biologists Alessandra Cambi and Koen van den Dries.

Immune cells crawl through our bodies all day long in search of dangerous viruses for example. To move easily through the complex structures of our tissues, these cells form hundreds of tiny feet, called podosomes. These feet sense what the cell encounters—kind of like how we test the temperature of pool water with our toes. Once a virus is identified, the immune cell retracts all its feet in a flash and races full speed to a lymph node to activate the body’s defense system.

Geckos

These cells resemble a miniature version of ourselves: they have a skeleton for stability, called the ‘cytoskeleton’, and little organs that regulate everything, the organelles. And feet, of course. ‘But they don’t have a brain’, says Alessandra Cambi, Professor of Cell Biology. So, their control isn't centralized. ‘The feet are formed very dynamically and locally, and then disappear again. All the materials needed are already present and reused, like the protein actin, which is the main component of the feet.’

So, cells with feet but no hands? ‘When we place immune cells on glass slides in the lab, these protrusions only appear at the bottom of the cells. So yes, feet’, explains cell biologist Koen van den Dries. ‘In the body, there’s no clear top or bottom, everything is 3D. But the feet always form on the side where there is something to sense, and that could even be upside down.’ A bit like how geckos can walk on the ceiling.

Periscope

Sometimes, immune cells even use these feet to remotely check the situation in the lungs or intestines. At the boundary with air or intestinal contents, there’s a wall of cells. Immune cells come from the underlying tissue and poke their feet between that wall to feel into the lung or gut, searching for invaders entering via air or food. It’s like a submarine using a periscope to safely observe the surface.

Not all cells have such feet. They mainly occur in cells that actively travel and manage processes in the body, often needing to break through barriers. ‘We do a lot of research on immune cells’, says Van den Dries. ‘But these feet also appear in other cell types, like those forming new blood vessels or breaking down bone. A stationary cell, like a liver cell, doesn’t have feet.’

Bouncy Ball

Alessandra and Koen have been studying the interaction between cells and their physical environment for years. Using the most advanced microscopes, they can observe things like the organization and movement of proteins in podosomes. Cambi: ‘Immune cells respond to the hardness, stretch, or stiffness of tissue. It’s like us: we walk very differently on asphalt than on sand, where our feet sink in.’ Van den Dries adds: ‘Or take putty, that children’s toy—it’s soft and squishy, but throw it hard against a wall and it turns into a bouncy ball. There’s a mechanical interaction with the hard surface that leads to a change in the putty. That’s how it works with cells too.’

This interaction of cells with materials can have quite an impact. ‘Imagine we have a stem cell, which is known to become any type of cell in the body. If we grow it on the hard surface of a plastic culture dish, it becomes a bone cell. On a soft surface, it becomes a fat cell’, Cambi explains. ‘We already know this for stem cells, but for immune cells, much less is known about how they respond to hard or soft materials.’

Lump

The researchers now know that immune cells encountering hard material sometimes seem to respond less effectively. And that’s inconvenient, because many processes in the body where an immune reaction is crucial involve tissue stiffening. Sick tissue is thicker and harder, like in fibrosis, inflammation, or tumors. Van den Dries: ‘We all know about the hard lump in the breast associated with breast cancer.’

In the lab, Cambi and Van den Dries are therefore studying the interaction between immune cells and cancer. In pancreatic cancer, a hard layer of material, called a fibrotic capsule, forms around the tumor. No immune cell can penetrate it, which impairs the immune response. ‘We want to learn how these cells react to hard tissue and which molecules are involved’, says Cambi. ‘That knowledge could one day help improve cancer therapies.’

Hard Plastic

Mechanical interaction is also highly relevant in immunotherapy. In this treatment, immune cells are taken from a patient’s blood and exposed in the lab to substances from the tumor so they can learn to respond. Then, they’re injected back into the patient to attack the tumor more actively. Currently, this culture process takes place in standard hard plastic lab dishes.

‘With our research, we’re trying to find out how much this hard plastic environment affects the activation of immune cells—and compare it with a soft environment’, says Van den Dries. ‘With that information, we hope to learn if and how we can improve the culture of immune cells for immunotherapy in the future.’ This principle of using a soft environment is already being tested. For example, in Australia, immune cells are reinjected around a tumor inside a special hydrogel that contains supporting substances for the immune cells, allowing them to better attack the tumor. Maybe one day we can use a hydrogel with mechanical properties that improves the work of immune cells around a tumor.

Drilling

Tumor cells themselves also use feet, but theirs are called invadopodia instead of podosomes. ‘There are differences’, says Cambi. ‘Podosomes are more dynamic and move faster than invadopodia. Whereas podosomes gently maneuver through tissue, invadopodia aggressively drill their way forward, helping cancer cells to spread. But structurally, they are similar—both are made of actin, the most common protein in our bodies that gives cells their firmness.’

The knowledge Van den Dries and Cambi gather from their fundamental research into immune cells is also useful in the context of cancer. ‘If we better understand how the ‘good feet’ of healthy cells work and what they respond to, we can better understand—and hopefully target—the ‘bad feet’ of cancer cells’, says Cambi. 

This story appeared before in Radbode #3, 2025.

 

See the Invisible

This year, Radboudumc will again be at the Kids Square during the Vierdaagsefeesten. Our cell biologists will welcome children into their pop-up lab and take them into a world so small that it’s invisible to the naked eye. Come make a "cellfie" of your own cells, see what mini-creatures, poop, and meat snacks look like under the microscope, trigger a color reaction with your own saliva, pipette like a real researcher, and learn how we use fluorescence to detect diseases. With Koen van den Dries, Marieke Willemse, Pieter Leermakers, and Gert-Jan Bakker. 

Where: Mariënburgplein, Nijmegen 

When: Sunday, July 13 and Monday, July 14, 1:00–5:00 PM

• Want to know more about these subjects? Click on the buttons below for more news.

  News homepage news & media