Pathway from Scientific Research

Schematics are presented, showing an intratumoral serotonin axis regulation of CD8 T cell antitumor immunity. In this model, SERT restrains CD8 T cell antitumor responses by inhibiting the CD8 T cell-autocrine 5-HT signaling pathway in a solid tumor. CD8 T cells are major producers of 5-HT (or serotonin) in the tumor microenvironment (TME). Upon recognition of tumor antigen, tumor-infiltrating CD8 T cells upregulate TPH1, which synthesizes 5-HT followed by releasing it into the TME to enhance T cell activation via 5-HT signaling. Meanwhile, tumor-infiltrating CD8 T cells also upregulate SERT, which acts in a negative-feedback loop to downregulate T cell activation by terminating 5-HT signaling via the reuptake of extracellular 5-HT from the TME. Blocking SERT activity using established SSRI antidepressants accumulates 5-HT in the TME, leading to the activation of the 5-HTR-MAPK-TCR signaling pathway and enhancement of CD8 T cell antitumor reactivities. This local serotonin accumulation induced by SSRIs resembles the effect observed in neuronal tissues, where SSRIs block the reuptake of serotonin by the presynaptic neuron, thereby accumulating serotonin secreted by the presynaptic neuron and stimulating neuronal activity. Note SSRIs exhibit different effects on systemic serotonin, where SSRIs block platelet uptake of gut enterochromaffin cell (EC)-produced serotonin and deplete serum serotonin.

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