Serotonin signaling and gut-immune crosstalk: the microbiome’s role in antitumor immunity.
“…Serotonin transporter inhibits cytotoxic CD8-positive T lymphocyte antitumor immunity by depleting serotonin within the tumor microenvironment…”
“…Serotonin transporter-blocking selective serotonin reuptake inhibitor antidepressants enhance cytotoxic CD8-positive T lymphocyte antitumor immunity and act synergistically with programmed cell death protein 1 immune checkpoint blockade therapy…”
To this end, here…
“…Tumor-infiltrating cytotoxic CD8-positive T lymphocytes were identified as the primary producers and mediators of a local, immunomodulatory serotonin signaling pathway independent of the gastrointestinal tract…”
“…Upon recognition of tumor antigens, tumor-infiltrating cytotoxic CD8-positive T lymphocytes upregulate tryptophan hydroxylase 1, which synthesizes serotonin followed by its release into the tumor microenvironment to enhance T lymphocyte activation via serotonin signaling…”
In short…
“…Serotonin transporter functions as an immune checkpoint that restricts cytotoxic CD8-positive T lymphocyte antitumor immunity…”
“…Inhibiting serotonin transporter activity using established selective serotonin reuptake inhibitor antidepressants results in the accumulation of serotonin in the tumor microenvironment, activating the serotonin receptor–mitogen-activated protein kinase–T cell receptor signaling pathway and enhancing cytotoxic CD8-positive T lymphocyte antitumor responses…”
‘…This identifies serotonin transporter as a potent negative regulator and highlights selective serotonin reuptake inhibitor antidepressants as promising candidates for next-generation cancer immunotherapy…’
“…Selective serotonin reuptake inhibitor antidepressants selectively target the serotonin transporter, avoiding interference with other neurotransmitter pathways…”
“…Analysis of existing human clinical data revealed that serotonin regulatory genes were most highly expressed in cytotoxic CD8-positive terminally differentiated effector memory T cells re-expressing CD45RA, a subset known for potent antitumor cytotoxicity…”
In conclusion and taken together…
‘…These findings illuminate the tumor-localized serotonin axis as a pivotal immunoregulatory mechanism and position serotonin transporter as a druggable immune checkpoint with clinical implications…’
“…Our study identified tumor-infiltrating cytotoxic CD8-positive T lymphocytes as the primary producers and mediators of a local, immunomodulatory serotonin signaling axis…”
“…The best-known role of serotonin in regulating inflammation has been established within the gut mucosal environment…”
‘…Given the microbiota’s established role in modulating peripheral serotonin levels, this axis likely intersects with gut microbial activity, suggesting therapeutic potential for microbiome-informed serotonin-based immunotherapies…’
“…This insight underscores the gut microbiota’s potential utility in future precision diagnostics and personalized therapies targeting serotonin-mediated pathways in cancer…”
Full text.
Serotonin transporter (SERT) inhibits CD8 T cell antitumor immunity by depleting intratumoral serotonin. SERT-blocking selective serotonin reuptake inhibitor (SSRI) antidepressants enhance CD8 T cell antitumor immunity and synergize with anti-PD-1, highlighting SSRIs as potential cancer immunotherapeutics.