T cells are the immune system's SWAT team. Their job is to constantly patrol the blood, lymphatic system, tissues, and organs. If they come across cells that are contaminated with or damaged by pathogens, they eliminate them. They can also recognise and destroy cancer cells. The problem, though, is that the tumour cells find ways of escaping this line of defence. Researchers around the world are working to prevent these evasive manoeuvres and harness T cells for targeted immunotherapies against cancer.
The labs led by Dr. Armin Rehm and Dr. Uta Höpken at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin have now identified a mechanism that tumour cells use to dodge the body's immune response. "In many cases, tumour cells read the EBAG9 gene especially often. The cells then produce a protein that protects them. But EBAG9 also influences the cells of the immune system because T cells produce it too. In T cells, EBAG9 inhibits the secretion of enzymes that act as poison to kill tumour cells," says Rehm. Writing in the journal JCI Insight, the researchers describe how they released this brake in mice: "We shut down the EBAG9 gene," says co-lead author Dr. Anthea Wirges, who works in Rehm's research group. "This meant we could stop EBAG9 being produced in the T cells and strengthen the immune response to cancer for the long term."
EBAG9 disarms immune cells
Scientists already know that cancer cells can outwit immune cells. This knowledge led to the development of checkpoint inhibitors, a type of immunotherapy that is already in clinical use. Checkpoint inhibitors make it hard for the cancer cells to trick T cells into thinking they're harmless. "But EBAG9 gives cancer cells another line of defence against our immune system," says Rehm. "It disarms the immune cells and stops them from secreting substances that would harm the cancer cells."
Cancer and infections trigger different immune responses
T cells recognise diseased or infected cells by the signalling molecules on their surface. When they detect these harmful structures, they differentiate between cytotoxic T cells and memory T cells. The cytotoxic T cells secrete proteins that punch holes in the target cell's membrane so that they can penetrate it and kill it by poisoning. Infected tissue also produces inflammatory signalling molecules, such as cytokines, that summon more T cells and cause them to mature into memory T cells. The memory cells record the immune response so that the immune system doesn't have to start from scratch every time the T cells detect a disease.
The idea: Create CAR T cells without an immune brake
Tumours don't cause inflammation in their early stages. Previously, scientists assumed that this was because T cells can't identify tumour cells very well. "Because they're produced by the body, tumour cells have very few surface molecules that are identifiable as foreign," says Höpken. But it seems as if these minimal differences are enough for the T cells to spot the tumour cells: When the researchers switched off EBAG9, the reaction was astonishing. "The uninhibited T cells eliminate tumour cells very early and very radically," notes Rehm. This also creates lasting protection against tumour cells. "The stronger the initial T cell reaction, the better the subsequent T cell memory," says Rehm.
Reference:
Armin Rehm, Anthea Wirges, Dana Hoser, Cornelius Fischer, Stefanie Herda, Kerstin Gerlach, Sascha Sauer, Gerald Willimsky, Uta E. Höpken. EBAG9 controls CD8+ T cell memory formation responding to tumor challenge in mice. JCI Insight, 2022; 7 (11)