Targeting monoamine oxidase A for T cell-based cancer immunotherapy

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 MoonMatteo Pellegrini, Lili Yang

Research output: Contribution to journalArticlepeer-review

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 cell-dependent manner. Combining MAOI and anti-PD-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.

Original languageEnglish (US)
Article numbereabh2383
JournalScience Immunology
Volume6
Issue number59
DOIs
StatePublished - May 2021
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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