Drug commonly used as an antidepressant helps fight cancer in mice

PICTURE: Shirley Xi Wang, Lili Yang, and Ryan Yu-Chen Wang found that mice became more able to fight melanoma and colon tumors when treated with MAOIs. view After

Credit: UCLA Large Stem Cell Research Center

A class of drugs called monoamine oxidase inhibitors are commonly prescribed to treat depression; the drugs work by increasing the levels of serotonin, the brain’s “happiness hormone”.

A new study by researchers at UCLA suggests that these drugs, commonly known as MAOIs, may have another health benefit: helping the immune system attack cancer. Their results are reported in two articles, which are published in the journals Scientific immunology and Nature Communication.

“MAOIs have never been linked to the immune system’s response to cancer before,” said Lili Yang, lead author of the study and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA . “What’s particularly exciting is that this is a very well-researched and safe class of drugs, so reusing it for cancer isn’t as difficult as developing a completely new drug on it. would be.”

Recent advances in understanding how the human immune system naturally searches for and destroys cancer cells, as well as how tumors try to evade this response, have led to new cancer immunotherapies – drugs that stimulate the activity of the immune system in an attempt to fight cancer.

In an effort to develop new immunotherapies against cancer, Yang and his colleagues compared immune cells from melanoma tumors in mice to immune cells from animals without cancer. The immune cells that had infiltrated the tumors had a much higher activity of a gene called monoamine oxidase A, or MAOA. The corresponding MAOA protein, called MAO-A, controls serotonin levels and is targeted by MAOI drugs.

“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 member of the UCLA Jonsson Comprehensive Cancer Center. “So it was exciting to find out that MAOA was so active in these tumor-infiltrating immune cells.”

Next, the researchers studied mice that did not produce MAO-A protein in immune cells. Scientists found that these mice better controlled the growth of melanoma and colon tumors. They also found that normal mice became more able to fight off these cancers when treated with MAOIs.

Investigating the effects of MAO-A on the immune system, researchers found that T cells – immune cells that target cancer cells for destruction – produce MAO-A when they recognize tumors, which shrinks their ability to fight cancer.

This discovery places MAO-A among 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 overreacting. attack healthy tissue in the body. Cancer is known to harness the activity of other previously identified immune checkpoints to evade attacks by the immune system.

In the Scientific immunology article, scientists report that MAOIs help block MAO-A function, which helps T cells overcome immune checkpoint and fight cancer more effectively.

But drugs also have a second role in the immune system, Yang found. Unwanted immune cells known as tumor associated macrophages often help tumors evade the immune system by preventing anti-tumor cells, including T cells, from mounting an effective attack. High levels of these tumor-associated immunosuppressive macrophages within a tumor have been associated with poorer prognoses for people with certain types of cancer.

But the researchers found that MAOIs block immunosuppressive macrophages associated with tumors, effectively destroying a tumor line of defense against the human immune system. This finding is reported in the Nature Communication paper.

“It turns out that MAOIs appear to both directly help T cells do their job and prevent tumor-associated macrophages from slowing down T cells,” Yang said.

Combine MAOIs with existing immunotherapies

Yang said she suspected MAOIs might work well in concert with a type of cancer immunotherapies called immune checkpoint blocking therapies, most of which work by targeting immune checkpoint molecules on the surface. immune cells. This is because MAOIs work on MAO-A proteins, which are inside cells and work differently from other known immune checkpoint molecules.

Studies in mice have shown that one of the three existing MAOIs – phenelzine, clorgyline or mocolobemide – alone or in combination with a form of immune checkpoint blocking therapy known as PD-1 blockers, could stop or slow the growth of colon cancer. and melanoma.

Although they did not test the drugs in humans, the researchers analyzed clinical data from people with melanoma, colon, lung, cervical and pancreatic cancer; they found that people with higher levels of MAOA gene expression in their tumors had, on average, shorter survival times. This suggests that targeting MAOA with MAOIs could potentially help treat a wide range of cancers.

Yang and coworkers are already planning additional studies to test the effectiveness of MAOIs in stimulating the response of human immune cells to various cancers.

Yang said MAOIs could potentially act on both the brain and immune cells of cancer patients, which are up to four times more likely than the general population to experience depression.

“We suspect that reuse of MAOIs for cancer immunotherapy may provide patients with both antidepressant and anti-tumor benefits,” she said.

The experimental combination therapy in the study has been used in preclinical testing only 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, with Yang, Xi Wang and Yu-Chen Wang as co-inventors.

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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 the Broad Stem Cell Research Center Ablon Scholars Program, the Magnolia Council of Tower Cancer Research Foundation and the National Institutes of Health, including a Ruth L. Kirschstein National Research Service Award.

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