Immunotherapy has revolutionized cancer care by training the immune system to detect and destroy tumors. For many patients, it works very well in shrinking tumors and sending cancer into remission, an undetectable state of cancer. But that remission is short-lived in some cases, and the cancer can return more resistant than before.

Researchers at the University of Chicago recently revealed that a small group of cancer cells, known as tumor-initiating stem cells (tSCs) hijack nearby neutrophils, turning them from attackers into protectors to survive attacks from the immune system which has been activated by immunotherapy.

The findings, published in Cancer Cell, not only explain a major cause of immunotherapy treatment failure, but also offer guidance for future treatments: combining immunotherapy with a common painkiller, such as aspirin, may prevent cancer relapse.

“Tumor-initiating stem cells are like a seed inside a fruit, covered by a protective layer of neutrophils,” said Yuxuan Miao, PhD, Associate Professor in the Ben May Department for Cancer Research and senior author of the study. “Immunotherapy destroys the fruit, but the seed is still protected and eventually regrows the tumor; our study shows how we might expose it.”

The protective shield around cancer’s core

The immune system’s first responders, neutrophils, are often the most abundant immune cells in a tumor. In early cancer development, they tend to suppress the immune response, helping tumors grow. But during immunotherapy, many neutrophils switch roles to become tumor-fighting agents, particularly under the influence of interferons, immune signals that enhance anti-tumor activity.

However, using advanced tools like single-cell RNA sequencing and spatial transcriptomics, researchers in Miao’s laboratory found that not all neutrophils transform from pro-tumor to anti-tumor agents. A small population located near tumor-initiating stem cells remained resistant to immunotherapy. Instead of activating to fight cancer, these neutrophils became even more suppressive, actively preventing T cells from entering the tumor.

“We were surprised to see two different populations of neutrophils exist in the tumor microenvironment and how they respond differently to immunotherapy treatments,” said first author Weijie Guo, PhD, Research Scientist in the Miao laboratory.

The researchers found that the tSCs release a fatty molecule called arachidonic acid which is transported to neutrophils and convert into prostaglandin E2 (PGE2), a well-known immune-suppressive signal. This process blocks the neutrophils’ ability to respond to interferons, the same immune triggers that normally reprogram them into cancer fighters.

“This was a striking example of cancer stem cells creating their own protective microenvironment by rewiring immune cells around them, turning potential fighters into bodyguards,” Miao said.

Timing is critical

Arachidonic acid is converted into PGE2 by an enzyme called cyclooxygenase (COX), the same enzyme targeted by drugs like aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Miao and his team hypothesized that using a COX inhibitor could block the immunosuppressive link between tSCs and neutrophils.

They tested this idea in mice with skin and head and neck squamous cell carcinoma, cancers known to contain tumor stem cells and respond to immunotherapy. When they treated the mice with either aspirin or immunotherapy alone, the tumors didn’t go away completely. But when the two treatments were combined, the tumors were eliminated.

The timing is also critical for combination therapies to be successful. Because neutrophils constantly cycle in and out of the tumor environment, the team found that giving the COX inhibitor before immunotherapy primed incoming neutrophils to be more responsive, ensuring they weren’t already “programmed” by prostaglandin signaling.

“Neutrophils don’t just flip from bad to good; the prostaglandin signaling has to be turned off when the interferon signals arrive,” Miao said. “That’s why the sequence and timing of treatment matters.”

Implications for future cancer therapies

Much like normal tissue stem cells, which maintain tissue health by dampening inflammation, cancer stem cells also deploy this mechanism to avoid destruction. The study adds to a growing body of research showing how tumor stem cells exploit the body’s own systems for self-preservation.

“We believe immune modulation is a deeply conserved program in stem cells, but in tumors, this program is hijacked to promote relapse,” Miao said.

The findings open the door to a new class of combination therapies that could enhance the effectiveness of current immunotherapies and potentially extend remissions or prevent relapse in cancers known to be driven by tumor stem cells.

“These are FDA-approved drugs we already have, and if we can apply them in the right way, at the right time, we may be able to make immunotherapy work even better and longer,” Miao said.

Future studies will focus on identifying additional mechanisms that block interactions between cancer-initiating stem cells and neutrophils, with the goal of developing improved cancer treatments. The team is also interested in examining whether similar interactions exist in other types of tumors, especially those that are hard to treat.

Source – University of Chicago