Repurposing antidepressants for cancer immunotherapy
Antibodies targeting immune checkpoints that restrain the antitumor effects of T cells are now a proven therapeutic approach for many forms of human cancer. The search for additional drug-targetable checkpoint molecules that regulate tumor immunity continues. Wang et al. identified monoamine oxidase A (MAO-A) as a gene up-regulated in tumor-infiltrating immune cells in mice. Tumor cells grew at a slower rate in mutant mice with decreased MAO-A expression. Inhibition of MAO-A activity by the antidepressant drug phenelzine enhanced the resistance of wild-type mice to tumor growth and exhibited synergy with antiтАУPD-1 treatment. These findings set the stage for further studies assessing the potential of repurposed MAO-A inhibitor drugs in the immunotherapy of cancer.
Abstract
Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain, where it breaks down neurotransmitters and thereby influences mood and behavior. Small-molecule MAO inhibitors (MAOIs) have been developed and are clinically used for treating depression and other neurological disorders. However, the involvement of MAO-A in antitumor immunity has not been reported. Here, we observed induction of the Maoa gene in tumor-infiltrating immune cells. Maoa knockout mice exhibited enhanced antitumor T cell immunity and suppressed tumor growth. MAOI treatment significantly suppressed tumor growth in preclinical mouse syngeneic and human xenograft tumor models in a T cellтАУdependent manner. Combining MAOI and antiтАУPD-1 treatments generated synergistic tumor suppression effects. Clinical data correlation studies associated intratumoral MAOA expression with T cell dysfunction and decreased patient survival in a broad range of cancers. We further demonstrated that MAO-A restrains antitumor T cell immunity through controlling intratumoral T cell autocrine serotonin signaling. Together, these data identify MAO-A as an immune checkpoint and support repurposing MAOI antidepressants for cancer immunotherapy.
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