Targeting monoamine oxidase A for T cell–based cancer immunotherapy
【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.
【Author】
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, Lili Yang
【Journal】
Science Immunology(IF：10.6) Time：2021-05-16
