Serotonin transporter inhibits antitumor immunity through regulating the intratumoral serotonin axis by Bo Li, James Elsten-Brown, Miao Li, ...,Arnold I. Chin, Matteo Pellegrini, Lili Yang instant download

Serotonin transporter inhibits antitumor immunity through regulating the intratumoral serotonin axis by Bo Li, James Elsten-Brown, Miao Li, ...,Arnold I. Chin, Matteo Pellegrini, Lili Yang instant download

SUMMARYIdentifying additional immune checkpoints hindering antitumor T cell responses is key to the development ofnext-generation cancer immunotherapies. Here, we report the induction of serotonin transporter (SERT), aregulator of serotonin levels and physiological functions in the brain and peripheral tissues, in tumor-infiltrating CD8 T cells. Inhibition of SERT using selective serotonin reuptake inhibitors (SSRIs), the most widelyprescribed antidepressants, significantly suppressed tumor growth and enhanced T cell antitumor immunityin various mouse syngeneic and human xenograft tumor models. Importantly, SSRI treatment exhibited significant therapeutic synergy with programmed cell death protein 1 (PD-1) blockade, and clinical data correlation studies negatively associated intratumoral SERT expression with patient survival in a range of cancers.Mechanistically, SERT functions as a negative-feedback regulator inhibiting CD8 T cell reactivities bydepleting intratumoral T cell-autocrine serotonin. These findings highlight the significance of the intratumoralserotonin axis and identify SERT as an immune checkpoint, positioning SSRIs as promising candidates forcancer immunotherapy.