Drugs that are regularly prescribed to treat depression in humans have been found to drastically halt the growth of pancreatic and colon cancers in mice. When combined with immunotherapy, these medications were capable of completely eliminating tumors in up to a third of cases, raising the prospect of more efficient therapies for some of the most difficult-to-treat cancers.
Describing their work in the journal Science Translational Medicine, a team of researchers set out to determine the role that the neurotransmitter serotonin plays in cancer development. Previous studies have indicated that peripheral serotonin in the blood may assist tumor cells in avoiding detection by the immune system, yet the mechanism behind this effect had until now remained unknown.
The study authors, therefore, began by inducing pancreatic and colon cancers in mice that had been genetically engineered to lack peripheral serotonin and found that these rodents tended to have better survival rates than regular mice with the same cancers. A more detailed analysis revealed that the tumors of serotonin-deficient mice contained higher concentrations of immune cells called killer T cells, resulting in their destruction.
At the same time, the tumors of engineered mice contained lower levels of an immunoinhibitory molecule called PD-L1, which blocks killer T cells and is known to play a role in helping cancers evade detection. For this reason, cancer immunotherapies tend to focus on inhibiting PD-L1, with varying success.
Based on their observations, the study authors concluded that peripheral serotonin enhances PD-L1 in cancer cells, which in turn impairs immune function and enables the growth of tumors. Moreover, because anti-depressant drugs like selective serotonin reuptake inhibitors (SSRIs) work by increasing serotonin levels in the brain but decreasing peripheral serotonin in blood platelets, the study authors speculated that these medications may help to reduce PD-L1 in cancer cells.
They, therefore, treated tumor-infested mice with a common SSRI called fluoxetine and found that this curbed the proliferation of cancer cells and enhanced survival rate. When this was combined with anti-PD-L1 immunotherapy, the researchers observed a significant increase in killer T cell concentrations within tumors, “enabling eradication of large established tumors in 20 percent of mice.”
The researchers then repeated the experiment using another antidepressant called telotristat, which inhibits the function of enzymes that synthesize peripheral serotonin. When combined with immunotherapy, this drug was found to eliminate tumors in 33 percent of mice.
“This class of antidepressants and other serotonin blockers cause immune cells to recognize and efficiently eliminate tumor cells again. This slowed the growth of colon and pancreatic cancers in the mice,” explained study author Pierre-Alain Clavien in a statement.
“Our results provide hope for cancer patients, as the drugs used are already approved for clinical use. Testing such drug combinations on cancer patients in clinical trials can be fast-forwarded due to the known safety and efficacy of the drugs.”