UCLA researchers are discovering that MAO inhibitors can activate the immune system to shrink different types of tumors.
A class of drugs called monoamine oxidase inhibitors is commonly prescribed to treat depression; medication works by increasing the level of serotonin, the brain’s “happiness hormone.”
A new study by UCLA researchers suggests that these drugs, commonly known as MAO inhibitors, may have another health benefit: helping the immune system fight cancer. Their findings are reported in two papers published in the journals Scientific immunology and Nature communication.
“MAO inhibitors had not been associated with the immune system̵
Recent advances in understanding how the human immune system naturally seeks out and destroys cancer cells, as well as how tumors try to avoid this response, have led to new cancer immunotherapies – drugs that increase the activity of the immune system to try to fight cancer.
In an attempt 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 much higher activity by a gene called monoamine oxidase A or MAOA. MAOAs equivalent protein, called MAO-A, controls serotonin levels and targets MAOIs.
“For a long time, people have been theorizing about the crosstalk 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 out that MAOA was so active in these tumor-infiltrating immune cells.”
Next, the researchers examined mice that did not produce MAO-A protein in immune cells. The researchers found that these mice were better at controlling the growth of melanoma and colon tumors. They also found that normal mice were more able to fight these cancers when treated with MAO inhibitors.
By digging into the effects of MAO-A on the immune system, the researchers discovered that T cells – the immune cells targeted by cancer cells for destruction – produce MAO-A when they recognize tumors, reducing their ability to fight cancer.
This finding places MAO-A among a growing list of molecules known as immune control points, 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 has been known to exploit the activity of other previously identified immune control points to avoid attack by the immune system.
IN Scientific immunology paper, the researchers report that MAO inhibitors help block the function of MAO-A, helping T cells overcome the immune checkpoint and more effectively fight cancer.
But the drugs also play a different role in the immune system, Yang found. Rogue immune cells known as tumor-associated macrophages often help tumors evade the immune system by preventing antitumor cells, including T cells, from mounting an effective attack. High levels of these immunosuppressive tumor-associated macrophages in a tumor have been associated with poorer prognosis for people with some types of cancer.
However, the researchers discovered that MAO inhibitors block immunosuppressive tumor-associated macrophages and effectively break down a line of defense that tumors have against the human immune system. This finding has been reported in Nature communication paper.
“It turns out that MAO inhibitors both seem to help T cells do their job and stop tumor-associated macrophages from inhibiting T cells,” Yang said.
Combination of MAO inhibitors with existing immunotherapies
Yang said she suspects MAO inhibitors may work well with a type of cancer immunotherapy called immune control point block therapy, most of which work by targeting immune control molecules on the surface of immune cells. This is because MAO inhibitors work on MAO-A proteins, which are inside the cells and function differently from other known immune control molecules.
Studies in mice showed that one of three existing MAOIs – phenelzine, clorgyline or mocolobemide – either alone or in combination with some form of immune checkpoint blocking therapy known as PD-1 blockers, could stop or slow the growth of Colon cancer and melanoma.
Although they have not tested the drugs in humans, the researchers analyzed clinical data from humans with melanoma, colon, lung, cervical and pancreatic cancers; they found that people with higher levels of MAOA gene expression in their tumors had, on average, shorter survival times. It suggests that targeting MAOA with MAO inhibitors could potentially help treat a wide range of cancers.
Yang and her collaborators are already planning further studies to test the effectiveness of MAO inhibitors in increasing the response of human immune cells to various cancers.
Yang said MAO inhibitors could potentially act on both the brain and immune cells of cancer patients, who are up to four times as likely to experience depression as the general population.
“We suspect that reusing MAO inhibitors for cancer immunotherapy may provide patients with dual antidepressant and antitumor benefits,” she said.
The experimental combination therapy in the study was used only in preclinical tests 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 University of California Regents, with Yang, Xi Wang and Yu-Chen Wang as co-inventors.
“Targeting Monoamine Oxidase A-Regulated Tumor-Associated Macrophage Polarization to Cancer Immunotherapy” by Yu-Chen Wang, Xi Wang, Jiaji Yu, Feiyang Ma, Zhe Li, Yang Zhou, Samuel Zeng, Xiaoya Ma, Yan-Ruide Li, Adam Neal, Jie Huang, Angela To, Nicole Clarke, Sanaz Memarzadeh, Matteo Pellegrini and Lili Yang, June 10, 2021, Nature communication.
DOI: 10.1038 / s41467-021-23164-2
“Targeting monoamine oxidase A for T cell-based cancer immunotherapy” by Xi Wang, Bo Li, Yu Jeong Kim, Yu-Chen Wang, Zhe Li, Jiaji Yu, Samuel Zeng, Xiaoya Ma, In Young Choi, Stefano Di Biase, Drake J. Smith, Yang Zhou, Yan-Ruide Li, Feiyang Ma, Jie Huang, Nicole Clarke, Angela To, Laura Gong, Alexander T. Pham, Heesung Moon, Matteo Pellegrini, and Lili Yang, May 14, 2021, Scientific immunology.
DOI: 10.1126 / sciimmunol.abh2383
The research was supported by Stop Cancer, Broad Stem Cell Research Center Rose Hills Foundation Innovator Grant and Stem Cell Training Program, UCLA Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center Ablon Scholars Program, Magnolia Council of the Tower Cancer Research Foundation. and the National Institutes of Health, including a Ruth L. Kirschstein National Research Service Award.