Williams Cancer Institute

MAO Inhibitors as Novel Cancer Immunotherapy Candidates

The serotonin signaling pathway has been extensively studied in neurons for decades. Serotonin, released by presynaptic neurons, communicates feelings of happiness and other behavioral changes by binding to the 5-hydroxytryptamine receptor (5-HTR) on postsynaptic neurons. After signaling, serotonin is reuptaken by presynaptic neurons to prevent overstimulation of 5-HTR, and is then broken down by the enzyme monoamine oxidase-A (MAO-A). This neurotransmitter pathway has led to the development of drugs to mitigate the effects of clinical depression and neurological disorders. One class of these drugs, MAO inhibitors (MAOIs), prevents MAO-A from breaking down serotonin upon reuptake into cells. Recent discoveries have revealed the potential of MAO-A as an immunomodulatory molecule and a candidate for immune checkpoint blockade (ICB) therapy.

ICB therapy has gained interest as oncology increasingly incorporates immunological approaches. Approved therapies like anti-PD-1/PD-L1 and anti-CTLA-4 have demonstrated significant remission rates, but limitations remain due to multiple immune checkpoint pathways. Therefore, identifying novel ICB candidates to augment current therapies is crucial. Studies are exploring the potential of MAOIs, already FDA-approved for depression, as ICB therapy candidates to improve treatment efficacy and broaden applicability across cancer types.

Recent studies have shown MAO-A upregulation in tumor-infiltrating immune cells, especially exhausted CD8 T cells, suggesting a negative regulatory role in anti-tumor immunity. Knockout studies in mice demonstrated suppressed tumor growth and increased cytotoxic lymphocyte activity in MAO-A-deficient mice. MAO-A knockout CD8 T cells produced higher serotonin levels, activating the immunostimulatory MAPK pathway. Additionally, MAO-A activity in tumor-associated macrophages (TAMs) correlated with immune suppression, suggesting a multifaceted role for MAO-A in the tumor microenvironment (TME).

Administering MAOIs in mice models significantly suppressed tumor growth, demonstrating their potential as ICB therapy candidates. Phenelzine, a commercially available MAOI, showed tumor-suppressive effects in multiple mouse models and a human xenograft model. Additionally, phenelzine inhibited TAM polarization, providing further support for MAOIs as ICB candidates.

Despite promise, MAOIs have associated adverse effects, including hypertension and liver toxicity. Strategies to mitigate side effects include nanoformulating MAOIs for targeted delivery to tumors, reducing systemic toxicity.

The discovery of MAO-A as an immune checkpoint offers exciting prospects for novel cancer therapies. While adverse effects pose challenges, optimizing drug delivery systems and exploring alternative serotonin pathway targets may enhance efficacy and minimize risks. MAOIs show potential as combination therapies with existing ICB treatments, offering new avenues for enhancing anti-tumor immune responses. Further research is needed to fully realize the therapeutic potential of MAOIs in cancer treatment.

Reference: Brown, J., Li, B., & Yang, L. (13 March 2022). MAOI antidepressants: Could they be a next-generation ICB therapy? https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.853624/full

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