In the fight against cancer, the immune system plays on two boards at the same time. On one hand, it needs to be aggressive enough to eliminate tumor cells. On the other, it must keep itself under control to avoid attacking the body’s own tissues. A new discovery led by Bruno Silva-Santos is helping researchers understand how this delicate “game” unfolds and could make immunotherapy more effective.

The study, published in the Journal of Experimental Medicine, reveals how a specific type of immune cell, regulatory T cells (Treg), can limit the activity of other cells with strong anti-tumor potential: gamma-delta T cells, which are a central focus of research in the laboratory at GIMM.

“We realized that regulatory T cells are actually suppressing our gamma-delta cells, not only in mouse models, but also in the human cells we produce in the lab,” explains Silva-Santos.

Gamma-delta cells have attracted growing interest in immunotherapy, particularly through so-called DOT cells — expanded and optimized versions generated through a process created and patented in the laboratory. However, the study shows that their effectiveness can be hindered by a surprisingly simple mechanism: competition for an essential growth factor, interleukin-2 (IL-2).

“Treg cells have a very high-affinity receptor for IL-2 and end up ‘stealing’ this factor from gamma-delta cells,” says the researcher. “Without IL-2, gamma-delta cells become ‘starved’ and can no longer proliferate or carry out their anti-tumor function.”

To test this hypothesis, the team used mouse models in which Treg cells could be selectively eliminated. The effect was immediate: gamma-delta cells accumulated inside tumors and became significantly more effective at controlling them. The phenomenon was observed in breast cancer and confirmed in colorectal cancer.

But the discovery did not stop at identifying the problem. It also pointed to a solution. The researchers used a synthetic molecule developed by the group of Gonçalo Bernardes, from Cambridge University, that mimics the action of IL-2 and directly activates its receptor.

“With this approach, we were able to bypass Treg-mediated suppression and restore the ability of gamma-delta cells to proliferate and fight the tumor,” explains Silva-Santos.

The results were also consistent in models using human cells. In immunodeficient mice carrying human breast tumors and treated with DOT cells, administration of this molecule significantly increased therapeutic efficacy.

For the researcher, this strategy has a clear advantage: simplicity. “We can increase efficacy without the need for genetic engineering [as required for CAR-T cells]. We simply combine DOT cells with this molecule.”

Still, the future may involve “comparing the efficacy of this new strategy with CAR-DOT cells, which are also under development.”

At its core, the research reveals a central tension within the immune system. Treg cells exist to protect the body from autoimmune diseases by controlling excessive immune responses. “It’s a double-edged system,” Silva-Santos emphasizes. “What protects us from autoimmunity can also compromise our ability to fight cancer.”

By identifying this mechanism – as well as a way to overcome it – the study opens new possibilities for immunotherapy, suggesting that treating cancer may increasingly depend on teaching the immune system when to stop holding itself back.