Serotonin transporter: a potential new immune checkpoint for cytotoxic T cells

In a recent publication in Cell, Yang and colleagues propose a novel role for the serotonin transporter (SERT) as an immune checkpoint in CD8 + T cells. 1 These findings highlight the therapeutic potential of selective serotonin reuptake inhibitors (SSRIs) as anti-tumor drugs.Serotonin (5-hydroxytrptamine, 5-HT) is a monoamine transmitter with various important roles in the body, including in the immune system.5-HT signaling can promote immune cell migration and regulate cytokine production. 2 Immune cells express a diverse repertoire of 5-HT receptors (5-HTR) on their cell surface.While all immune cells respond to exogenous 5-HT, T lymphocytes (in particular CD8 + or cytotoxic T cells) also produce serotonin.Indeed, T cells possess the complete machinery for 5-HT synthesis, storage, degradation, and secretion. 3It has been demonstrated in vitro that during T-cell receptor (TCR) signaling, the synthesis and release of 5-HT increases. 2This leads to autocrine stimulation of 5-HTRs and enhanced T-cell activation. 2 Thus, serotonin appears to act as an accessory signal to help stimulate CD8 + T cells. 2,3Li et al. propose that SERT functions as a novel immune checkpoint in CD8 + T cells. 1 Checkpoints evolved as a homeostatic mechanism to constrain an overactive immune response.However, these signals can also be exploited (enhanced) by cancer cells to suppress immune function.Li et al. report upregulated SERT in tumor-infiltrating CD8 + T cells compared with nave cells, suggesting the tumor microenvironment alters T-cell serotonin signaling.Treatment with SSRIs, fluoxetine and citalopram, increased the number of intratumor CD8 + T cells and enhanced the cytotoxic functionality of these cells.Crucially, SSRI treatment also led to smaller tumor sizes and prolonged survival in both mouse syngeneic and human xenograft tumor models.SERT KO mice showed similar results as the SSRI treatments, supporting SERT as the SSRI target.Other cells, including cancer cells themselves, express SERT.Therefore, to identify a specific role for CD8 + T cells, Li et al. performed adoptive transfer experiments, transferring either normal or SERT-deficient immune systems/ CD8 + T cells into recipient mice with irradiated immune systems.Once again, disrupting SERT in these mouse models led to enhanced CD8 + T-cell function (less cell exhaustion and greater killing capacity) and a smaller tumor size.To identify a cellautonomous effect, they turned to cell culture experiments.In response to TCR stimulation, SERT KO CD8 + cells exhibited greater proliferation, cytokine generation, and cytotoxic function compared with wild-type CD8 + T cells.Similar results were obtained when wild-type CD8 + cells were stimulated in the presence of the SSRI, fluoxetine.