A class of drugs called monoamine oxidase inhibitors are commonly prescribed to treat depression; the drugs work by increasing levels of serotonin, the brain’s “happy hormone.”
A new study by UCLA researchers suggests those drugs, commonly known as MAOIs, may have another health benefit: helping the immune system attack cancer. Their findings are reported in two articles published in the journals Science Immunology and nature communication.
“MAOIs had not been previously associated with the immune system’s response to cancer,” said Lili Yang, senior author of the study and member of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCLA. “What’s especially exciting is that this is a very well-studied and safe class of drugs, so reusing it for cancer isn’t as challenging as developing a completely new drug.”
Recent advances in understanding how the human immune system naturally seeks out and destroys cancer cells, as well as how tumors try to evade that response, has led to new cancer immunotherapies — drugs that boost the activity of the immune system to try to fight cancer.
In an effort to develop new cancer immunotherapies, Yang and her colleagues compared immune cells from melanoma tumors in mice with immune cells from cancer-free animals. Immune cells that had infiltrated tumors had a much higher activity of a gene called monoamine oxidase A or MAOA. MAOA’s corresponding protein, called MAO-A, regulates serotonin levels and is the target of MAO inhibitors.
“For a long time, people have theorized about the crosstalk between the nervous system and the immune system and the similarities between the two,” said Yang, who is also an associate professor of microbiology, immunology, and molecular genetics at UCLA and a member of UCLA’s Jonsson Comprehensive Cancer Center. Center. “So it was exciting to find that MAOA was so active in these tumor-infiltrating immune cells.”
The researchers then studied mice that did not make MAO-A protein in immune cells. The scientists found that those mice were able to better control the growth of melanoma and colon tumors. They also found that normal mice became better able to fight those cancers when treated with MAO inhibitors.
The researchers dug into the effects of MAO-A on the immune system and found that T cells — the immune cells that target cancer cells for destruction — produce MAO-A when they recognize tumors, which reduces their ability to fight cancer.
That discovery puts MAO-A on a growing list of molecules known as immune checkpoints, which are molecules produced as part of a normal immune response to prevent T cells from overreacting or attacking healthy tissue in the body. Cancer is known to misuse the activity of other previously identified immune checkpoints to evade attacks by the immune system.
In the Science Immunology paper, the scientists report that MAO inhibitors help block the function of MAO-A, which helps T cells overcome the immune checkpoint and fight the cancer more effectively.
But the drugs also have a secondary role in the immune system, Yang found. Rogue immune cells known as tumor-associated macrophages often help tumors evade the immune system by preventing anti-tumor cells, including T cells, from launching an effective attack. High levels of those immunosuppressive tumor-associated macrophages in a tumor have been associated with worse prognosis for people with some types of cancer.
But the researchers found that MAO inhibitors block immunosuppressive tumor-associated macrophages, effectively breaking down one line of defense tumors have against the human immune system. That finding is reported in the nature communication paper.
“It turns out that MAO inhibitors seem to both directly help T cells do their job and prevent tumor-associated macrophages from putting the brakes on T cells,” Yang said.
Combining MAOIs with Existing Immunotherapies
Yang said she suspects MAO inhibitors may work well in combination with a type of cancer immunotherapies called immune checkpoint blockade therapies, most of which work by targeting immune checkpoint molecules on the surface of immune cells. That’s because MAO inhibitors act on MAO-A proteins, which are located in cells and function differently than other known immune checkpoint molecules.
Studies in mice showed that each of the three existing MAO inhibitors — phenelzine, clorgyline, or mocolobemide — alone or in combination with a form of immune checkpoint blocking therapy known as PD-1 blockers, can stop or slow the growth of colon cancer and prevent melanoma. .
Although they didn’t test the drugs in humans, the researchers analyzed clinical data from people with melanoma, colon, lung, cervical and pancreatic cancers; they found that people with higher levels of MAOA gene expression in their tumors had shorter survival times on average. That suggests that targeting MAOA with MAO inhibitors could potentially help treat a wide variety of cancers.
Yang and her collaborators are already planning additional studies to test the effectiveness of MAO inhibitors in boosting the response of human immune cells to various cancers.
Yang said MAO inhibitors could potentially act on both the brain and immune cells in cancer patients, who are up to four times more likely than the general population to experience depression.
“We suspect that reusing MAOIs for cancer immunotherapy may provide patients with dual antidepressant and antitumor benefits,” she said.
The experimental combination therapy in the study was only used in preclinical testing and has not been studied in humans or approved by the Food and Drug Administration as safe and effective for use in humans. The newly identified therapeutic strategy is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, co-invented by Yang, Xi Wang and Yu-Chen Wang.
The research was supported by Stop Cancer, the Broad Stem Cell Research Center Rose Hills Foundation Innovator Grant and Stem Cell Training Program, the UCLA Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center Ablon Scholars Program, the Magnolia Council of the Tower Cancer Research Foundation and the National Institutes of Health, including a Ruth L. Kirschstein National Research Service Award.
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