Prof. dr. Arnon Kater has been awarded a €2.5 million ERC Advanced Grant to investigate why cancer-fighting immune cells lose their effectiveness over time. The highly competitive grant from the European Research Council will enable Kater and his team to pursue an ambitious five-year research program that could reshape our understanding of cancer immunotherapy.

Immunotherapy, which uses a patient’s own immune cells to target cancer cells, can sometimes produce remarkable results. However, this approach is not effective for many types of cancer. The prevailing explanation is that immune cells become exhausted and are no longer sufficiently activated. Researcher and hematologist Arnon Kater believes the opposite may be true: immune cells may become hyperactivated and, as a result, fail to function properly. With an ERC Advanced Grant, he will investigate how this process develops, how these dysfunctional immune cells can be restored, and how this knowledge can be translated into new immunotherapies.

With a €2.5 million ERC Advanced Grant from the European Research Council, Kater, Professor of Hematology at Amsterdam UMC, will spend the next five years investigating why T cells—the immune system’s primary cancer-fighting cells—gradually lose their ability to function when they encounter tumor cells. Understanding this process is one of the most important questions in cancer immunology.

Constant activation

Much of today’s research focuses on improving the way T cells are stimulated to kill cancer cells. The prevailing view is that tumors fail to provide these immune cells with sufficient signals to trigger an effective response. As a result, nearly all immunotherapies developed to date aim to enhance T-cell activation.

However, research by Kater and his colleagues points to a fundamentally different mechanism.

“We see that these T cells are not receiving too few signals at all. In fact, they are continuously exposed to activation signals. Under normal circumstances, such as after vaccination, these signals quickly subside. If they do not, the constant activation disrupts the immune cell’s energy supply.”

Patient-derived cells

This overstimulation damages the mitochondria—the cell’s energy-producing structures—causing the immune cell’s energy metabolism to become dysregulated. As a result, T cells lose their ability to divide and survive for only a short period of time.

The SPARC project will investigate step by step how this process develops. Importantly, the researchers will primarily use both cancer cells and immune cells derived directly from patients, rather than model systems or mouse cells. The team will also employ advanced microscopy, genetic screening technologies, and novel techniques that allow them to monitor the energy state of individual T cells.

Promising indications

The research is not only aimed at understanding the problem but also at identifying a potential solution. Kater’s research group has found indications that these dysfunctional T cells can be restored to a healthy and functional state. Understanding how this works and how this knowledge can be applied in future immunotherapies forms a key part of the project.

A new generation of immunotherapies

The project will initially focus on chronic lymphocytic leukemia, a type of blood cancer. However, the researchers expect that the same mechanisms play a role in many other forms of cancer as well. If this proves to be the case, the findings could provide the foundation for a new generation of immunotherapies in which patients’ immune cells remain effective for longer periods, allowing tumors to be targeted more sustainably rather than only temporarily.

The ERC Advanced Grant is one of Europe’s most prestigious research funding schemes and is awarded to established researchers with innovative ideas that have the potential to significantly advance their field.