For typical illnesses, the body’s immune system is a robust, pathogen-killing machine. It provides a general defense against harmful germs while also adapting and producing antibodies that target specific bacteria or viruses. After fighting off an infection like the flu, the body produces regulatory T cells, also known as Tregs. These cells send signals to slow down the immune system, usually an essential process preventing the body from attacking itself or causing too much collateral damage.

But a disease like breast cancer plays by different rules.

It forces the body to produce too many Tregs, and this overproduction suppresses the immune system, rendering it unable to stop tumor growth. Researchers have long known about Tregs and their association with a poor response to traditional cancer therapies. Since oncologists can’t target these immunosuppressive cells, they rely on therapies that attack cancer cells directly. However, these approaches have significant drawbacks.

“Traditional treatments that attack cancer cells with chemotherapy and radiation come with limitations,” said Associate Professor Erik Nelson. “They can damage healthy tissues near the tumor, which can cause side effects, and further weaken an already depleted immune system, leaving the body susceptible to other infections.”

The limitations of standard therapies inspire Nelson and his team, which includes CCIL Deputy Director Paul Hergenrother, Kenneth L. Rinehart Jr. Endowed Chair in Natural Products Chemistry, and Professor of Chemistry, and graduate student Hashni Epa Vidana Gamage, to pursue novel immunotherapies—treatments that engage the immune system, priming it to kill cancer cells.

“Realistically, we must target cancer cells and engage the immune system to move toward curative treatments,” said Nelson.”

Nelson, Hergenrother, and Gamage​ recently published two papers in Cancer Letters focusing on NR0B2. This protein can potentially stop or slow regulatory T cells from suppressing the immune system.

The first paper shows that NR0B2 may be able to alter how immune cells communicate with T cells and inform what type of T cell ultimately emerges. Simply put, more NR0B2, fewer immune-suppressive T cells.

Think of breast cancer’s effect on the immune system like the workings of a Rube Goldberg machine, a complex mechanism to carry out a simple task through a succession of events that trigger one after another. Breast cancer causes a series of interactions within the body that prevent the immune system from working properly.

Instead of destroying breast cancer’s Rube Goldberg functionality (which could harm a patient’s health in other ways), Nelson and his team are attempting to tweak the process, known to researchers as a pathway, just enough to alter the outcome. Suppose you’ve played a game like Mousetrap. In that case, the slightest variation in how the ball rolls down the stairs or the diver jumps in the diving pool, can break the process and cause a malfunction – or fewer Tregs and a better ability to fight tumor growth.

“NR0B2 fine-tunes almost every aspect of the pathway. Rather than hitting the Rube Goldberg machine with a sledgehammer, it regulates things subtly. This subtleness is essential to create an approach that limits potential side effects and negative impacts on a patient.

Because of NR0B2’s promise, Nelson and Gamage sought Hergenrother’s expertise in developing anticancer compounds against hard-to-treat cancers.

“The Cancer Center at Illinois does an excellent job of promoting interdisciplinary research and facilitating effective collaborations,” said Nelson. “Since that collaborative fabric is in place, Hashni and I were able to approach Paul and initiate these studies efficiently.”

The second paper explores how the team worked with Hergenrother to develop new derivatives of NR0B2 for testing. Vidana Gamage screened those variations, looking for variations that could slow or stop immune suppression with low toxicity.

“It is a back-and-forth process. We screen derivatives against models in a petri dish, take that data back to the lab, and they would design more compounds. That’s how we ended up with a compound that may target the pathway that activates suppression of the immune system,” said Vidana Gamage.

The group details the discovery of an inverse correlation between NR0B2 and a marker for Tregs called FOXP3, meaning an increased amount of NR0B2 led to less immune system suppression.

“The first animal study we published in the paper was the turning point,” said Vidana Gamage. It was soon after we returned to the lab after the onset of COVID-19. You’re prepared for failure when a study goes from the petri dish to an animal. Sometimes, they translate, sometimes not. We got to that point for this study, and ‘Oh, my gosh. It worked!'”

While this study focuses on breast cancer, the research team has explored its potential on other types of cancer, like melanoma or lung cancer, and have seen similar results.

“Because we’re altering the immune system and not targeting the cancer cells themselves, we think it’s potentially applicable to all solid tumors that are difficult to treat with conventional therapies,” said Nelson.

Nelson, Hergenrother, and Gamage will continue investigating NR0B2’s effects on the immune system and its potential as a viable therapeutic for cancer patients.

“The vision is to position this for the treatment of tumors, either as a single agent or combined with other immunotherapies,” said Vidana Gamage. We’re continuing to refine our understanding of how the compound works in animal models as we work to make this approach viable for human clinical trials.”

Editor’s Notes:

• Erik Nelson is a co-leader of the CCIL’s Cancer Engineering and Biological Systems research program and an associate professor in molecular and integrative physiology, nutritional sciences, and the Beckman Institute for Advanced Science and Technology. He is also an affiliate of the Carl R. Woese Institute for Genomic Biology.
• Paul Hergenrother is the CCIL’s deputy director, a professor of chemistry, and the director of the Carl R. Woese Institute for Genomic Biology.
• Hashni Epa Vidana Gamage​ was a Ph.D. student in Erik Nelson’s lab within the School of Molecular and Cellular Biology. She successfully defended her thesis over the summer.
• The paper “NR0B2 re-educates myeloid immune cells to reduce regulatory T cell expansion and progression of breast and other solid tumors” is available online: https://doi.org/10.1016/j.canlet.2024.217042
• The paper “Development of NR0B2 as a therapeutic target for the re-education of tumor-associated myeloid cells” is available online: https://doi.org/10.1016/j.canlet.2024.217086

This article was written by Florence Lin, Jessica Clegg, and Tyler Wolpert.