Messing with a dual-purpose protein that can both stimulate and modulate antitumor immunity would seem a tricky way to try enhancing cancer immunotherapy. Yet that is what a team of scientists based at the University of Bonn decided to do. They focused on a protein called IκB-kinase β (IKKβ). This protein, which occurs naturally in the body, has long been known to activate the immune system. It also promotes the development of immune cells, including regulatory T cells (Tregs), which serve to temper the immune response.
The scientists found that by inhibiting IKKβ, they could suppress Tregs and thereby prevent them from restraining killer T cells. Fortunately, it turns out that killer T cells, or cytotoxic T lymphocytes (CTLs), are less reliant on IKKβ for survival and expansion than are Tregs.
Details of the scientists’ work appeared October 17 in the journal Cell Reports, in an article entitled “Prolonged IKKβ Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells.” The article presents evidence, from experiments with mice, that prolonged IKKβ inhibition decimates circulating Tregs and improves CTL responses when commenced after tumor vaccination. These findings, the article’s authors suggest, indicate that IKKβ represents a druggable checkpoint.
“We report that mature Tregs continue to require NF-κB signaling through IκB-kinase β (IKKβ) after thymic egress,” wrote the article’s authors. “Pharmacological IKKβ inhibition reduced Treg numbers in the circulation by ∼50% and downregulated FoxP3 and CD25 expression and STAT5 phosphorylation. In contrast, activated cytotoxic T lymphocytes (CTLs) were resistant to IKKβ inhibition because other pathways, in particular nuclear factor of activated T cells (NFATc1) signaling, sustained their survival and expansion.”
Many tumors possess mechanisms to avoid destruction by the immune system. For instance, they misuse the natural “brakes” in the immune defense mechanism, which normally prevent an excessive immune response. The University of Bonn scientists have now been able to take off one of these brakes.
Killer T cells are a powerful weapon of the immune system. Following a viral infection, for instance, they swarm out in huge numbers and destroy all of the infected body cells. Their destructive power is also directed toward cancer cells—at least in principle. Many tumors have actually developed mechanisms that allow them to outmaneuver this defensive weapon. To do this, tumors abuse the so-called Tregs, for example. These are also part of the immune system, but fulfill an opposite function there: They suppress the immune response and thus prevent killer T cells from attacking healthy tissue in the body.
Tumors exploit this by pretending to belong to the body's own tissue. They can thus be protected to a certain degree by the Tregs. “We have now found a way to kill off the Tregs,” explains Christoph Heuser, a doctoral candidate at the Institute of Experimental Immunology at the University of Bonn. “We were thus able to significantly increase the impact of the killer T cells.”
The study focuses on a protein produced naturally in the body called IKKβ, which has been known for long to promote the activation of immune cells. It is thus considered an immunostimulant. “We have now blocked IKKβ in a test tube with the help of a pharmaceutical ingredient,” says Heuser's colleague Dr. Janine Gotot. “The Tregs died off afterward. However, the killer T cells survived and even gained in impact because they were no longer inhibited by the Tregs.”
Using mice with skin cancer, the researchers then tested whether the IKKß inhibitor could be suitable for tumor treatment. Today this cancer is treated by vaccination and by immunotherapies, but these measures are often not effective enough. However, the researchers treated the rodents with the IKKß inhibitor shortly after the vaccination. Following around two weeks of treatment, the number of Tregs fell by half. The response of the killer T cells to the tumor was correspondingly stronger. The cancer growth was delayed significantly by this, and the animals survived for longer.
“Nevertheless, complete healing cannot be achieved solely by inhibiting IKKß,” relativized Christian Kurts, M.D., director of the Institute of Experimental Immunology at the University of Bonn. “By combining with other immunological active pharmaceutical ingredients, it may, however, be possible to stimulate the immune system to more effectively combat the cancer.”
The Tregs are actually only one element among many others with which the body keeps its immune cells in check. Experts also refer to these braking mechanisms as “immunological checkpoints.” In recent years, researchers have succeeded in releasing these brakes using suitable inhibiting substances (the “checkpoint inhibitors”). “This approach has already revolutionized the treatment of cancer,” says Kurts.