A class of drug called monoamine oxidase inhibitors is commonly prescribed to treat depression;
the medications work by boosting levels of serotonin, the brain's "happiness hormone."
A new study by UCLA researchers suggests that those drugs, commonly known as MAOIs, might
have another health benefit: helping the immune system attack cancer.
Their findings are reported in two papers, which are published in the journals Science
Immunology and Nature Communications.
The researcher says 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.
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 immune system's activity to try to fight cancer.
In an effort to develop new cancer immunotherapies, the researchers compared immune cells from
melanoma tumors in mice to immune cells from cancer-free animals.
Immune cells that had infiltrated tumors had much higher activity of a gene called monoamine
oxidase A, or MAOA.
MAOA's corresponding protein, called MAO-A, controls levels of serotonin and is targeted
by MAOI drugs.
Next, the researchers studied mice that didn’t produce MAO-A protein in immune cells.
The scientists found that those mice were better at controlling the growth of melanoma
and colon tumors.
They also found that normal mice became more capable of fighting those cancers when treated
with MAOIs.
Digging in to the effects of MAO-A on the immune system, the researchers discovered
that T cells — the immune cells that target cancer cells for destruction — produce MAO-A
when they recognize tumors, which diminishes their ability to fight cancer.
That 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 attacking healthy tissue in the body.
Cancer has been known to exploit the activity of other previously identified immune checkpoints
to evade attack by the immune system.
In the Science Immunology paper, the scientists report that MAOIs help block the function
of MAO-A, which helps T cells overcome the immune checkpoint and more effectively fight
the cancer.
But the drugs also have a second role in the immune system.
Rogue 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 those immunosuppressive tumor-associated macrophages in a tumor have been associated
with poorer prognoses for people with some types of cancer.
But the researchers discovered that MAOIs block immunosuppressive tumor-associated macrophages,
effectively breaking down one line of defense that tumors have against the human immune
system.
That finding is reported in the Nature Communications paper.
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.
Although they haven’t tested 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.
That suggests that targeting MAOA with MAOIs could potentially help treat a broad range
of cancers.