Early life exposure to antidepressants shapes anti-tumor immunity 4527

Abstract Description Early onset colorectal cancer (CRC) incidence rates have significantly increased over the past two decades, but the underlying mechanisms are poorly understood. Antidepressants, like selective serotonin reuptake inhibitors (SSRIs), are among the largest increases in prescription medications during pregnancy over the past decades. Our work recently elucidated that neonatal gut bacteria produce high levels of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) and limit 5-HT breakdown by inhibiting monoamine oxidase expression in the neonatal intestine. Using a maternal SSRI mouse model, we show that postnatal exposure to maternal SSRI significantly elevates gut 5-HT levels and changes the gut microbiome composition in neonatal mice. Continuous SSRI exposure starting from nursing reduced progression of colon tumors in male mice, but not in females; this was associated with increased tumor infiltrating T cells producing interferon-gamma and Perforin and decreased tumor infiltrating B cells in SSRI-exposed male mice. Tumor progression was unaffected in gnotobiotic mice harboring gut bacteria from SSRI-exposed mice or in mice that were exposed to SSRI as adults. Altogether, we determined that early life SSRI exposure in the intestine enhances antitumor immunity in a sex- and age-dependent manner. Our findings may uncover an early life factor (maternal SSRI use) that could be leveraged to lower CRC risk or help in finding therapeutic targets to enhance antitumor immunity. Funding Sources NIH/NCATS 2KL2-TR-2385 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)