Cooperating T cells clear tumor cells more effectively

Tumor cells die when they are damaged by T cells several times in a short period of time, while they can still recover after a single blow. Scientists from the Radboudumc, together with an international team, have demonstrated this in a publication in Nature Communications. This discovery provides new starting points for improving therapy against cancer.

'The soldiers of the immune system', so-called cytotoxic T cells, can single-handedly kill a single blood cancer cell, sometimes as many as 20 times a day. But in larger tumors, a single T cell's attack on a tumor cell rarely leads to the tumor cell's death. Scientists at the Radboudumc now show that this is successful if several T cells work together. They also show in detail how exactly T cells cause damage, and how tumor cells then try to repair that damage.

No bazooka

Peter Friedl, Professor of Microscopic Imaging of the Cell at the Radboudumc: "We already knew that T cells and tumor cells regularly make contact with each other. But what exactly happens between the cells? We see that during half of the interactions, the T cell damages the tumor cell by causing holes in the cell membrane, cracks in the nuclear membrane and damage to the DNA. This should not be thought of as shooting with a bazooka, but more like cutting with a small knife. If a T cell cuts only once, then the tumor cell can still repair the damage, just as we can recover from a cut. But more damage in a short time can kill the tumor cell."

The researchers used skin cancer cells and watched the contact with T cells with a special microscope for living cells. They also developed 3D computer models that simulated the interactions. The results show that tumor cells die when they have been targeted at least three times by a T cell within three hours. This can be three times by the same T cell, but in 80% of the cases multiple T cells are involved. With a low concentration of T cells, the tumor cell receives less damage and is therefore more likely to survive. In general, therefore, the more T cells are near the tumor cell, the better.

Stimulating damage

This research provides new starting points for improving therapy against cancer. Friedl: "We have shown that several blows that individually do not lead to the death of the tumor cell can do so together. You want to stimulate that further. For example, with drugs that ensure longer binding of the T cell to the tumor cell via so-called activating checkpoints. These drugs bind to the T cell and stimulate the immune response against tumor cells. We have already shown that you can then make a single T cell do serial damage to the same tumor cell. You can also give very low doses of chemotherapy or radiation, so that the damage adds up to the damage caused by the T cells. We expect that this could render the tumor cell more vulnerable so it dies off faster."

Video: Immune cells attack tumor

In this video we see how tumor cells (blue) are attacked by cytotoxic T cells (green). In yellow you see the damage caused by the T cells. At the end, the tumor cell breaks down.

About the publication

This research was published in Nature Communications: Cytotoxic T cells are able to efficiently eliminate cancer cells by additive cytotoxicity. Bettina Weigelin, Annemieke Th. den Boer, Esther Wagena, Kelly Broen, Harry Dolstra, Rob J. de Boer, Carl G. Figdor, Johannes Textor and Peter Friedl.
 

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