Smoking Tied to Higher Risk and Worse Outcomes in Pancreatic Cancer, Study Finds

A new study may explain why smokers are more likely to develop pancreatic cancer and why their disease tends to be more aggressive than in nonsmokers.

Researchers at the University of Michigan Health Rogel Cancer Center have identified a specific immune cell that responds to toxins found in cigarettes. When these toxins bind to the cell, it triggers the release of a protein called interleukin-22 (IL22), which accelerates tumor growth in mice with pancreatic cancer. The team also discovered a highly suppressive immune cell that not only fuels this growth but also shuts down the body’s ability to fight tumors.

The findings were published in Cancer Discovery, a journal of the American Association for Cancer Research.

In the study scientists exposed mice with pancreatic tumors to a chemical commonly found in cigarettes and other environmental toxins. They wanted to see how the carcinogen affected IL22, which previous research suggested plays a role in the tumor microenvironment.

“It dramatically changed the way the tumors behave. They grew much bigger, they metastasized throughout the body. It was really quite dramatic,” said senior author Dr. Timothy L. Frankel, co-director of the Rogel and Blondy Center for Pancreatic Cancer.

Further tests revealed that the carcinogen only spurred tumor growth in mice with intact immune systems, suggesting the immune response was key. The team then uncovered a role for IL22-producing T-regulatory cells — immune cells previously linked to autoimmune diseases but not to pancreatic cancer.

“These T-regulatory cells have the ability to both make IL22 but also massively suppress any anti-tumor immunity. It’s a two-pronged attack,” Frankel explained. “When we eliminated all the Treg cells from these mice, we reversed the entire ability of the cigarette chemical to let the tumor grow.”

The researchers confirmed their results in human immune cells and in samples from pancreatic cancer patients. Smokers with pancreatic cancer had more T-regulatory cells than nonsmokers, aligning with the animal studies.

They also found that an inhibitor blocking the cigarette chemical was effective at shrinking tumors.

“If we are able to inhibit the super suppressive cells, we might also unlock natural anti-tumor immunity,” Frankel said. “This could be even further activated by current immunotherapies, which do not work well in pancreatic cancer because of the immunosuppressive environment.”

The study suggests future therapies could target this pathway and that treatment may need to be tailored for smokers.

“There’s a potential that we need to treat smokers who develop pancreatic cancer differently,” Frankel said. “We may also need to screen smokers more closely for pancreatic cancer development. There is not a great screening mechanism, but people who smoke should be educated about symptoms to look out for and consider referrals to a high-risk clinic.” Frankel also emphasized prevention: “People with a family history of pancreatic cancer or with other pancreatic inflammatory diseases should avoid smoking.”