Immunotherapy has largely failed as a treatment for cancer of the pancreas, and researchers have zeroed in on a key reason.
Pancreatic tumors reprogram immune cells that normally shut down tumor-killing cells, according to a team at Oregon Health & Science University in Portland.
“Pancreatic cancer is incredibly resistant to most therapies,” said senior author Katelyn Byrne, an assistant professor at the OHSU School of Medicine.
“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,” she added in a news release.
Immunotherapies like immune checkpoint inhibitors have revolutionized the treatment of melanoma and lung cancer. But they haven’t shown the same benefit for pancreatic cancer, the third-leading cause of cancer-related death in the U.S.
The presence inside pancreatic tumors of large numbers of regulatory T cells (Tregs) is a big reason why. Simply put, they overtake immune cells capable of killing tumors.
“If there are a lot of them in a tumor, it’s extremely hard to get an anti-tumor immune response going,” Byrne said.
She and her team reported this month in the journal Immunity on mouse tests of an experimental immunotherapy.
Known as agonistic CD40, it works differently from standard checkpoint inhibitors.
Instead of targeting one immune signal, it activates a broader response.
And it didn’t just activate tumor-killing cells, researchers were surprised to find, it converted them into cells that supported anti-tumor activity.
“We didn’t expect this,” Byrne said. “Cells that were shutting down the immune reaction suddenly started supporting tumor killing.”
The findings help explain why many immunotherapies don’t work in pancreatic cancer and suggest a possible solution.
Treatments may need to attack with a double-whammy — activating the immune system while overcoming the tumor’s own ability to shut it down.
While results of studies in animals often differ in the humans, these discoveries could be meaningful in treating a disease in which most patients stop responding to available treatments over time, researchers said.
Combo strategies could make immunotherapy useful, Byrne said.
The research also points to opportunities to combine immune-based treatments with newer cancer drugs, such as KRAS inhibitors, that directly attack pancreatic cancer cells but still rely on immune support.
“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.”
Clinical trials using this combo therapy should be underway in humans within the next several years, she said.
Her lab is now working to better understand the communication between immune cells inside pancreatic tumors and to find out whether the reprogrammed cells offer long-term protection.
Research shows that Black Americans have the highest pancreatic cancer incidence and mortality rates, often 30-70 percent higher than those of other racial groups. They are also more likely to be diagnosed at advanced stages, receive less aggressive treatment, and experience poorer overall survival rates.
Several structural inequities drive these disparities, including:
Even after adjusting for socioeconomic factors that may influence pancreatic cancer outcomes for Black patients, studies show Black patients continue to experience higher mortality rates and lower rates of surgical resection.
The study’s findings highlight how research on the tumor microenvironment could shape future treatment selection and therapeutic development for pancreatic cancer.
Potential clinical implications include
Clinicians will play a significant role in translating these discoveries into equitable care pathways, particularly for Black patients, who continue to experience poorer outcomes in pancreatic cancer.
Black patients remain underrepresented in immunotherapy and precision oncology studies. When clinical trials lack diverse participant populations, the external validity and generalizability of emerging therapies may be limited.
Several barriers can reduce enrollment of Black patients in medical research, including:
Clinicians can help improve trial diversity by discussing available studies with eligible patients and helping connect them to enrollment resources.
This study adds to the longstanding evidence that pancreatic cancer remains largely resistant to immunotherapy. Researchers believe the tumor microenvironment may play a central mechanistic role in the development of more effective immunotherapeutic strategies.
Black patients continue to face disproportionately higher incidence and mortality rates in pancreatic cancer, underscoring the need for earlier diagnosis, timely treatment, and equitable access to emerging therapies.
Increasing Black participation in clinical trials may help improve the development and evaluation of future therapies. Clinicians have an opportunity to support more equitable pancreatic cancer through early intervention, referral, and research engagement.
More information
There’s more about pancreatic cancer at the Pancreatic Cancer Action Network.
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