News items New culture method reveals how cancer cells bypass immune system
5 July 2021

Scientists at Radboudumc have developed a method that allows them to study how cancer cells and immune cells influence each other. This provides more knowledge about how some cancer cells can block the immune response. The research was recently published in scientific journal Cancer Immunology Research.

Our body can arm itself against cancer cells. To do so, it deploys so-called cytotoxic T-cells. These "soldiers of the immune system" shoot holes in cancer cells, causing damage inside. If cells have many of these cytotoxic events, they die. Tumors, however, can bypass the immune system by inhibiting the action of the T-cell soldiers. This makes it harder for the immune system to fight the cancer cells.

Although it has long been known how T-cells kill cancer cells, it was not yet known how some cancer cells fight back. Scientists at the Radboudumc have therefore developed a new method to investigate this process. This shows that some cancer cells can stop the immune system's attack by stopping the T-cells from shooting holes in the cancer cells.

Three-dimensional culturing

For their research, the scientists used a new three-dimensional method, growing cancer cells and immune cells simultaneously. In a transparent culture dish, the cancer cells sit on the bottom, topped by a three-dimensional tissue-like matrix that contains the T-cells. Just as in the body, the T-cells go looking for the cancer cells, and a microscope can be used to make the interaction between the two types of cells visible with very high precision.

That three-dimensional culture method allows the researchers to show at the cellular level how the T-cells go about killing cancer cells. "They attach to their target and fire one or more shots," says Jeroen Slaats, a researcher in the Department of Cell Biology at Radboud university medical center. "Then it's the turn of the next T-cell, which does the same. The T-cells work together as a team, until eventually the cancer cell has been hit so many times that it dies."

Shooting holes

Some cancer cells can nullify that T-cell-killing property of T-cells by blocking calcium channels in the T-cell, Slaats explains. "We see that the T-cells stick to the cancer cells, but they are less successful at shooting holes. As a result, the cancer cells don't die or don't die until later." As if the cancer cell takes the gun away from the T-cell.

Now that the researchers have clarified where in the process the hitch is, they can work on solving the problem. But that's still in the future. "We want to work on controlling the processes in the cancer cell that affect the effectiveness of the T-cell," says Peter Friedl, professor at the Department of Cell Biology at Radboud university medical center. "With a future medicine, it may become possible to make the T-cell fire bullets at the cancer cell again. And if we can give them the weapon back, we can even make T-cells fire more or bigger bullets."

Understanding the mechanism

But it's a long way from that. The researchers emphasize that they are not directly looking for a medicine that will suddenly allow T-cells to attack those cancer cells again. "Our work does not provide a direct solution to a problem," says Friedl. " It's important to first understand what's going wrong before we want to influence it. We now have a better understanding of how tumor cells mislead the T cells."

The first dot on the horizon for the researchers is to offer patients more personalized treatments. "We can use this method to grow a patient's cancer cells and study them much more closely than was previously possible," Friedl says. "Besides understanding the mechanism of cancer cells, that is the added value of our research at the moment."

About the publication in Cancer Immunology Research

Metabolic Screening of Cytotoxic T-cell Effector Function Reveals the Role of CRAC Channels in Regulating LethalQ2 Hit Delivery – Jeroen Slaats, Cindy E. Dieteren, Esther Wagena, Louis Wolf, Tonke K. Raaijmakers, Jeroen A. van der Laak, Carl G. Figdor, Bettina Weigelin, and Peter Friedl.

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