Immunotherapy may get a boost – ScienceDaily

T cells are usually very good at eliminating diseased cells. But they seem to fail when it comes to cancer cells. in JCI Insightthe MDC team led by Armin Rehm and Uta Hopkin describe what suppresses this immune function, and how they can release the brakes and enhance the immune response against cancer.

T cells are the SWAT team of the immune system. Their job is to constantly monitor the blood, lymphatic system, tissues, and organs. If cells come across contaminated or damaged with pathogens, they eliminate them. They can also recognize and destroy cancer cells. The problem, however, is that cancer cells find ways to escape this line of defense. Researchers around the world are working to block these evasive maneuvers and harness T cells for targeted immune therapies against cancer.

Laboratories led by Dr. Armin Rehm and Dr. Uta Hopkin at the Max Delbrück Center for Molecular Medicine at the Helmholtz Association (MDC) in Berlin have identified a mechanism that cancer cells use to evade the body’s immune response. “In many cases, cancer cells read the EBAG9 gene specifically often. The cells then produce a protein that protects them. But EBAG9 also affects immune system cells because T cells produce it as well. In T cells, EBAG9 inhibits the release of enzymes that act as a toxin to kill.” cancerous cells,” says Rehm. Writing in the magazine JCI InsightThe researchers described how they released these brakes in mice: “We shut down the EBAG9 gene,” says co-lead author Dr. Anthea Wiergs, who works in the Rehm research group. “This means that we can stop the production of EBAG9 in T cells and strengthen the immune response to cancer in the long term.”

EBAG9 desensitizes immune cells

Scientists already know that cancer cells can overwhelm immune cells. This knowledge led to the development of checkpoint inhibitors, a type of immunotherapy already in clinical use. Checkpoint inhibitors make it difficult for cancer cells to trick T cells into thinking they are harmless. “But EBAG9 gives cancer cells another line of defense against our immune system,” says Rehm. It disarms immune cells and prevents them from secreting substances that can harm cancer cells.

Rehm and Höpken have long suspected that EBAG9 inhibits T cells. In 2009, Rehm developed a mouse model in which researchers turned off the EBAG9 gene. “The mice’s immune system worked better without EBAG9 and they were able to fight infection more effectively,” Rehm says. Hopkin’s team then crossed EBAG9-null mice with another genetically modified mouse model that spontaneously developed leukemia. “We observed these doubly modified mice over a long period of time,” Hopkin says. “Their tumors developed much more slowly than in mice with EBAG9.”

Cancer and inflammation trigger different immune responses

Wierges examined the effects of the EBAG9 gene on T cells using single-cell RNA sequencing and bioinformatic methods. In addition to confirming that EBAG9 suppresses the T-cell response, the data also demonstrated that the immune response to cancer differs from that induced by infection.

“Knowledge about how the immune system ‘memory’ develops comes from models of infection. It cannot be transferred in a 1:1 ratio to tumors,” Rehm says. T cells recognize diseased or injured cells by signaling molecules on their surface. When they detect these harmful structures, they differentiate into cytotoxic T cells and memory T cells. Cytotoxic T cells secrete proteins that puncture the membrane of the target cell so that they can penetrate and kill it by sepsis. The injured tissue also produces inflammatory signaling molecules, such as cytokines, that call upon more T cells and make them mature into memory T cells. Memory cells record the immune response so that the immune system does not have to start from scratch every time T cells detect disease.

The idea: to create CAR T cells without immune suppression

Tumors do not cause inflammation in their early stages. Previously, scientists theorized that this was because T cells could not recognize cancer cells well. “Because the body produces it, cancer cells have very few surface molecules that can be recognized as foreign,” Hopkin says. But these minimal differences seemed to be enough for the T cells to detect cancer cells: When the researchers turned off EBAG9, the reaction was startling. “Unrestricted T cells eliminate cancer cells very early and very radically,” Rehm notes. This also creates permanent protection against cancer cells. “The stronger the initial T-cell reaction, the better the subsequent T-cell memory,” says Rehm.

“Based on these findings, we now want to develop CAR T cells without EBAG9 as an immunotherapy for leukemia,” Wirgs says. CAR stands for chimeric antigen receptor – a synthetic receptor that detects cancer cells and is incorporated into a patient’s T cells. When patients get the CAR T cell infusion, it provides their bodies with cells capable of fighting cancer. MDC researchers expect that CAR T cells would be more functional without EBAG9. Although it will take some time before the cells reach the clinical trial stage, it may be worth the wait: “We’re not just hoping that this treatment will result in more effective treatments for leukemia and lymphoma. Hopefully, that’s going to cure them,” Rahm says.


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