Antibiotics Make PDA Treatment More Effective in Mice

Patients with pancreatic cancer have significantly more gut bacteria than they are supposed to, which plays a role in the rate of tumor growth. The gut bacteria in these patients is overwhelmed with species that prevent the immune system from fighting tumor cells, according to a study published by Cancer Research.

The study was conducted in mice and patients with pancreatic ductal adenocarcinoma (PDA), a cancer that typically becomes fatal within 2 years.

The authors found they could slow the growth of tumors by removing bacteria from the gut and pancreas of mice with antibiotics. This also allowed them to reprogram immune cells to identify cancer cells, according to the study.

Treatment with antibiotics was also found to improve the efficacy of checkpoint inhibitors, an immunotherapy that previously failed in pancreatic cancer patients, according to the study authors.

In patients with PDA, gut bacteria travels to the pancreas through the pancreatic duct, disrupting its normal function of removing digestive juices into the intestines, according to the study. The abnormal microbiome gives off cellular components that promote tumor growth by essentially shutting down the immune system.

Although the genes that cause rapid cell growth in the pancreas change the immune response and allow for new bacterial species, the authors noted that outside factors, including diet, medication, and other diseases, may also be responsible for bacterial changes.

The bacteria found among patients with pancreatic cancer emits cell membrane components and proteins that suppress microphages, the immune cells of the pancreas, according to the study. The researchers tested the effect of antibiotic use in mice with PDA and found that treatment to remove bacteria resulted in a stronger immune response and a 50% decrease in the number of cancer cells.

The authors also found that certain bacteria in pancreatic tumors can activate immune cell sensors, called “checkpoints,” signaling them to turn off. These sensors typically prevent the body from attacking its own cells, but cancer cells can signal them to turn off and prevent the immune system from destroying the cancer.

Checkpoint inhibitors work by turning off checkpoints, allowing the immune system to recognize cancer cells again, according to the study.

“Adding antibiotics improved the performance of a checkpoint inhibitor in a mouse model of PDA, as shown by an increase in T cells that could attack the tumors,” said co-author Mautin Hundeyin, MD. “Our study confirmed that, similar to what has been observed in patients with pancreatic cancer, checkpoint inhibition alone did not protect mice. This may be because, in the immunosuppressive environment of the tumor, there are too few immune cells around to be activated.”

The next step, according to the authors, will be to conduct a clinical trial that tests whether combining antibiotics and checkpoint inhibitors can effectively treat patients with PDA.

“Our results have implications for understanding immune-suppression in pancreatic cancer and its reversal in the clinic,” said co-author Deepak Saxena, PhD. “Studies already underway in our labs seek to confirm the bacterial species most able to shut down the immune reaction to cancer cells, setting the stage for new bacteria-based diagnostic tests, combinations of antibiotics and immunotherapies, and perhaps for probiotics that prevent cancer in high-risk patients.”