A Bold Insight into Immunotherapy's Blind Spot and a Practical Fix
Immunotherapy has dramatically changed cancer care by teaching the immune system to recognize and attack tumors. For many patients, this approach shrinks tumors and drives cancer into remission, an undetectable state that can last for a while. Yet, in some cases, that remission fades, and cancer returns more resistant than before.
Researchers at the University of Chicago have uncovered a hidden mechanism behind this relapse. A small subset of cancer cells, known as tumor-initiating stem cells (tSCs), latches onto nearby neutrophils and reprograms them from tumor fighters into protectors. This covert alliance helps the cancer survive immunotherapy and eventually regrow.
The study, published in Cancer Cell, not only sheds light on a key reason why immunotherapy sometimes fails but also points to a potential, practical enhancement: pairing immunotherapy with a common pain reliever like aspirin to cut relapse rates.
“Tumor-initiating stem cells act like a seed inside a fruit, shielded by a layer of neutrophils,” said Yuxuan Miao, PhD, associate professor in the Ben May Department for Cancer Research and senior author of the work. “Immunotherapy can destroy the fruit, but the seed remains protected and can eventually sprout again; our findings suggest ways to expose it.”
The protective barrier around cancer’s core
Neutrophils are often the most abundant immune cells present in tumors. In early cancer development, they can dampen the immune response and aid tumor growth. However, when immunotherapy is used, many neutrophils switch roles and help fight the cancer, especially under interferon signals that boost anti-tumor activity.
Using cutting-edge techniques like single-cell RNA sequencing and spatial transcriptomics, the researchers found that not all neutrophils flip from pro-tumor to anti-tumor. A small subset near the tumor-initiating stem cells stayed resistant to immunotherapy. Instead of becoming active defenders, these neutrophils became more suppressive, blocking T cells from infiltrating the tumor.
“We were surprised to discover two distinct neutrophil populations in the tumor microenvironment and that they respond differently to immunotherapy,” said Weijie Guo, PhD, the study’s first author and a research scientist in Miao’s lab.
The tSCs release arachidonic acid, a fatty molecule that travels to neutrophils and is converted into prostaglandin E2 (PGE2), a powerful immune-suppressive signal. This process prevents neutrophils from responding to interferons, the very triggers that would normally reprogram them into cancer-fighting agents.
“This illustrates how cancer stem cells construct their own protective niche by reconfiguring surrounding immune cells into bodyguards,” Miao noted.
Timing is everything
Arachidonic acid is turned into PGE2 by the enzyme cyclooxygenase (COX)—the same target of aspirin and other NSAIDs. The team hypothesized that blocking COX could interrupt this immunosuppressive chain between tSCs and neutrophils.
Testing this idea in mouse models of skin and head-and-neck cancers, which harbor tSCs and respond to immunotherapy, yielded striking results. Treatments with aspirin or immunotherapy alone reduced tumors but didn’t eradicate them. When combined, tumors were fully eliminated.
Crucially, timing mattered. Neutrophils continuously move in and out of the tumor environment, so administering a COX inhibitor before immunotherapy primed incoming neutrophils to respond effectively rather than being pre-programmed by prostaglandin signals.
“Neutrophils don’t simply flip from bad to good; the prostaglandin signal must be silenced when interferon signals arrive,” Miao explained. “The sequence and timing of treatments are key.”
Implications for future cancer therapies
Like normal tissue stem cells that help keep inflammation in check, cancer stem cells deploy this tactic to dodge destruction. The study adds to a growing body of evidence that tumor stem cells hijack the body’s own systems to promote relapse.
“We believe immune modulation is a deeply conserved program in stem cells, but in tumors it’s commandeered to support relapse,” Miao said.
These findings open the door to new combination therapies that could boost current immunotherapies, potentially extending remissions or preventing relapse in cancers driven by tumor stem cells.
“The drugs involved are already FDA-approved. If used correctly and at the right moments, they may make immunotherapy work better and for longer,” Miao said.
Future work will seek to uncover additional mechanisms by which cancer-initiating stem cells and neutrophils interact, aiming to develop even more effective treatments. The team is also interested in whether similar interactions occur in other hard-to-treat tumors.
This study, “Tumor-Initiating Stem Cells Fine-tune the Plasticity of Neutrophils to Sculpt a Protective Niche,” was supported by start-up funds from the University of Chicago, Cancer Research Foundation Breakthrough Board, Cancer Center Support Grant, pilot grants from the University of Chicago Medicine Comprehensive Cancer Center, and grants from the NIH, American Cancer Society, V Foundation, AACR, and the Cancer Research Foundation.
Additional authors include researchers from the University of Chicago, Kyoto University, Mahidol University, the University of Duisburg-Essen, ISAS-e.V., Centro Nacional de Investigaciones Cardiovasculares Carlos III, Universidad Carlos III de Madrid, and Yale University, among others.
