Reprogramming regulatory T cells could help immunotherapy work in pancreatic cancer

Researchers at Oregon Health & Science University have uncovered a key reason why immunotherapy has largely failed in pancreatic cancer—and identified a promising strategy to overcome that resistance. The study, published in the journal Immunity, shows that pancreatic tumors actively reshape their immune environment by co-opting regulatory immune cells that normally shut down tumor-killing cells. By reprogramming those cells, the research reveals a potential pathway to make immunotherapy effective against one of the deadliest and most treatment-resistant cancers.

“Pancreatic cancer is incredibly resistant to most therapies,” said the study’s senior author, Katelyn Byrne, Ph.D., assistant professor of cell, developmental and cancer biology in the OHSU School of Medicine and member of the OHSU Brenden-Colson Center for Pancreatic Care. “Even when we know the immune system is capable of long-lasting protection, it’s been very difficult to get that response to work in this disease.”

Immune checkpoint inhibitors and other immunotherapies have transformed care for cancers such as melanoma and lung cancer, but they have shown little benefit for pancreatic cancer. One major reason, Byrne said, is the presence of large numbers of regulatory T cells, or Tregs, inside pancreatic tumors.

“Tregs are very suppressive immune cells,” Byrne said. “If there are a lot of them in a tumor, it’s extremely hard to get an anti-tumor immune response going.”

In many pancreatic cancers, these regulatory cells overtake immune cells capable of killing tumors, effectively neutralizing immunotherapy before it can work.

Suppressive cells turned tumor fighters

In the new study, Byrne and team tested an experimental immunotherapy in mouse models known as agonistic CD40, which works differently from standard checkpoint inhibitors. Rather than targeting a single immune signal, the therapy broadly activates the immune response upstream.

Byrne said the researchers were surprised to find out that activating the immune system this way didn’t just stimulate tumor-killing cells—it also reprogrammed regulatory T cells, converting them from immune suppressors into cells that support anti-tumor activity.

“We didn’t expect this,” Byrne said. “The therapy doesn’t directly target Tregs, but as a secondary effect of turning on the immune response, those Tregs changed their behavior. Cells that were shutting down the immune reaction suddenly started supporting tumor killing.”

The team’s findings help explain one reason why many immunotherapies haven’t worked in pancreatic cancer and point to a possible solution: Treatments may need to both turn on the immune system and overcome the tumor’s own ability to shut it down.

This could be especially significant for pancreatic cancer, where most patients eventually stop responding to available treatments. Combination strategies could finally make immunotherapy viable, Byrne says.

“Until now, if a tumor had a lot of Tregs and didn’t respond to checkpoint inhibitors, we didn’t have many other immunotherapy options,” Byrne said. “This approach could make resistant tumors more permissive, meaning they could respond to immunotherapy when they previously couldn’t.”

The research also creates opportunities to combine immune-based treatments with newer cancer-targeted drugs, such as KRAS inhibitors, which directly attack pancreatic cancer cells but still rely on immune support for durable responses.

“You can imagine hitting the cancer cell with a targeted drug while also reprogramming the immune environment around it,” Byrne said. “That combination could be much more effective than either approach alone.”

Personalized treatment

The study also highlights the importance of patient-specific immune differences. Some pancreatic tumors contain many immune cells that are suppressed by Tregs, while others lack immune cells altogether—suggesting that no single therapy will work for every patient.

“The goal is to match the treatment to the biology of the patient’s tumor,” Byrne said. “We think we can identify whether a patient’s tumor is rich in regulatory T cells using the same biopsy that’s already done for diagnosis.”

Byrne said clinical trials in humans using this combination therapy should be underway within a few years. Her lab is now working to further map the complex communication between immune cells inside pancreatic tumors and to determine whether the reprogrammed cells provide long-term immune protection.

“The more we understand every step of this process, the more precisely we can intervene,” Byrne said. “That’s what will allow us to move closer to durable, long-lasting immune responses for pancreatic cancer patients.”