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Monoamine oxidase inhibitors are a type of medicine used to treat depression. They operate by increasing levels of serotonin, the brain’s “happy hormone.”
According to a recent UCLA study, such medications, also known as MAOIs, may offer another health benefit: aiding the immune system’s fight against cancer. Two publications detailing their findings were published in the journals Science Immunology and Nature Communications.
“MAOIs had not been linked to the immune system’s response to cancer before,” said Lili Yang, senior author of the study and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “What’s especially exciting is that this is a very well-studied and safe class of drug, so repurposing it for cancer isn’t as challenging as developing a completely new drug would be.”
New cancer immunotherapies have been developed as a result of recent developments in understanding how the human immune system naturally searches out and eliminates cancer cells, as well as how cancers try to dodge that response.
Yang and her colleagues compared immune cells from melanoma tumors in mice to immune cells from cancer-free animals in order to create novel cancer immunotherapies. The activity of a gene termed monoamine oxidase A, or MAOA, was substantially greater in immune cells that had penetrated tumors. MAO-A, the homologous protein to MAOA, regulates serotonin levels and is targeted by MAOI medicines.
“For a long time, people have theorized about the cross-talk between the nervous system and the immune system and the similarities between the two,” said Yang, who is also a UCLA associate professor of microbiology, immunology and molecular genetics and a member of the UCLA Jonsson Comprehensive Cancer Center. “So it was exciting to find that MAOA was so active in these tumor-infiltrating immune cells.”
The researchers next investigated mice that didn’t develop MAO-A in their immune cells. The researchers discovered that those mice were better at suppressing melanoma and colon tumor development. They also discovered that when mice were given MAOIs, they became more capable of battling cancer.
When the researchers looked into the effects of MAO-A on the immune system, they discovered that when T cells — immune cells that target cancer cells for destruction — detect tumors, they create MAO-A, which reduces their capacity to fight cancer.
MAO-A joins a growing list of immune checkpoint molecules, which are molecules generated as part of a normal immune response to keep T cells from overreacting and destroying healthy tissue in the body. To resist the immune system’s onslaught, cancer has been found to leverage the activities of several previously established immunological checkpoints.
Yang discovered that the drugs also have a second function in the immune system. Tumor-associated macrophages are rogue immune cells that enable tumors to avoid the immune system by blocking anti-tumor cells, such as T cells, from launching an effective attack. High numbers of immunosuppressive tumor-associated macrophages in a tumor have been linked to a worse prognosis in persons with certain types of cancer.
But according to the researchers, MAOIs disrupt immunosuppressive tumor-associated macrophages, essentially breaking down one line of protection that tumors have against the human immune system. This discovery is detailed in the publication published in Nature Communications.
“It turns out that MAOIs seem to both directly help T cells do their job, and stop tumor-associated macrophages from putting the brakes on T cells,” Yang said.
According to Yang, MAOIs may perform well in combination with immune checkpoint blockade treatments, a kind of cancer immunotherapy that works by targeting immune checkpoint molecules on the surface of immune cells.
Studies in mice indicated that any of three current MAOIs — phenelzine, clorgyline, or mocolobemide — could stop or reduce the growth of colon cancer and melanoma whether used alone or in conjunction with PD-1 blockers, a kind of immune checkpoint blockade medication.
The researchers evaluated clinical data from persons with melanoma, colon, lung, cervical, and pancreatic cancer and discovered that those with greater levels of MAOA gene expression in their tumors had shorter survival durations on average. This shows that using MAOIs to target MAOA might help cure a wide variety of cancers.
“We suspect that repurposing MAOIs for cancer immunotherapy may provide patients with dual antidepressant and antitumor benefits,” she said.