Targeting serotonin transporter boosts tumor-fighting T cells

Abstract

In this issue of Cell, Yang and colleagues demonstrate that autocrine activation of serotonin receptors on tumor-infiltrating CD8⁺ T cells enhances antitumor immunity. Modulating serotonin signaling may provide a new approach to therapy for cancer. Serotonin-targeting drugs such as SSRIs and others, developed to fight depression, may thus be repurposed for cancer immunotherapy.

Serotonin, which arose early in evolution, has like many of evolution’s successful themes been modularly repeated; serotonin is found in virtually all animals and in most vertebrate organs.¹ Although popularly thought of as a brain neurochemical (a “happy hormone”), serotonin acts throughout the body as a multifunctional molecule with roles in autocrine, paracrine, neurocrine, and endocrine signaling.² Recently, serotonin has also been implicated in cancer development and anti-cancer therapy.³ Serotonin’s role in cancer is not only limited to effects on tumor cells but also involves the complex tumor microenvironment, which includes tumor-infiltrating immune cells. The activation of these immune cells using checkpoint inhibitors to promote anti-tumor activity has become a modern direction of anti-cancer treatment.⁴ Immune cells also express a variety of serotonin receptors, which regulate immune cell functions.⁵

In this issue of Cell, Yang and colleagues⁶ demonstrate that autocrine serotonergic stimulation of cell surface receptors on tumor-infiltrating CD8⁺ T cells facilitates the reaction of these cells against the tumors. Enhancement of the autocrine serotonergic stimulation of CD8⁺ T cells synergizes with checkpoint inhibitors to potentiate anti-tumor therapy. These observations benefit from the mechanism by which serotonin-mediated actions are controlled. Serotonin is rapidly catabolized by intracellular enzymes such as monoamine oxidase, and being membrane-impermeant at physiological pH, it relies on the serotonin reuptake transporter (SERT) for cellular uptake. SERT, therefore, is the major inactivator of extracellular serotonin. Inhibition or deletion of SERT thus enhances the strength and duration of serotonergic actions. Li et al. report that SERT is induced in tumor-infiltrating CD8⁺ T cells and that selective serotonin reuptake inhibitors (SSRIs) suppress tumor growth, enhance T cell antitumor immunity, and, importantly, exert therapeutic synergy with a checkpoint inhibitor.⁶ Analysis of clinical data also shows an inverse correlation between SERT expression and patient survival in a variety of cancers. The study concludes that SERT is a negative feedback regulator that inhibits CD8⁺ T cell reactivity by lowering the functional concentration of autocrine serotonin in contact with T cell serotonin receptors within tumors.

The emerging picture shows that serotonin plays a somewhat surprising role as an important modulator of interactions between tumors and the CD8⁺ T cells that infiltrate them, with SERT functioning as a brake on antitumor CD8⁺ T cell activity. The study by Li et al. opens new avenues for cancer immunotherapy by harnessing the potential of SSRIs and related agents to invigorate the immune response.⁶ As our understanding of paracrine and autocrine crosstalk in the tumor microenvironment continues to grow, a large array of drugs designed for the brain may find new life in the fight against cancer. Repurposing of these pharmaceuticals, many of which have already received FDA clearance, may speed the pace of success in treating cancer by providing a leap forward in clinical translation.

Despite the great value of potentially being able to tap the already approved array of psychotherapeutic serotonin drugs for assistance in cancer therapy, there is reason for some caution. Tumor-infiltrating CD8⁺ T cells may not be the only cells in the microenvironment of a tumor that produce serotonin or express serotonin receptors. Some tumors may incorporate normal cells into the tumor microenvironment, such as nerves that produce and secrete serotonin; moreover, tumors may occur in body regions, such as the gastrointestinal mucosa, where serotonin promotes growth of both normal cells⁷ and tumors.⁸ Fan and co-workers have reported that serotonin enhances self-renewal and proliferation of colorectal cancer stem cells⁸ and that tumor growth is impeded either by depriving the cancer of its source of serotonin or by pharmacological antagonism of the relevant serotonin receptors on the cancer stem cells (5-HT_1B, _1D, and _1F). Interestingly, the biosynthesis of the serotonin that promotes growth of the normal gastrointestinal mucosa and colorectal cancer depends on tryptophan hydroxylase 2 (TPH2),^3,9 which is expressed by serotonergic neurons that are attracted to the tumors,⁸ rather than TPH1, which is the TPH isoform that tumor-infiltrating CD8⁺ T cells⁶ and all other non-neuronal cells express.³ Therapy designed to enhance the autocrine action of serotonin on tumor-infiltrating CD8⁺ T cells, such as an SSRI to inhibit SERT, may thus counterproductively enhance the ability of serotonin to stimulate tumor growth.

Both opportunities and challenges have thus emerged from studies of serotonin and cancer. The opportunity, emanating from the work of Yang and her co-workers,⁶ is that a wide variety of pharmacological agents have been developed to inhibit or enhance serotonin’s actions¹⁰; these agents can potentially be mobilized as novel therapies for cancer. The challenge, illustrated by the neurocrine serotonergic stimulation of the growth of colorectal cancer,⁸ is that the therapeutic use of serotonin drugs may, in some tumors, be complicated. Benefits from the enhancement of the autocrine anti-cancer actions of serotonin on tumor-infiltrating CD8⁺ T cells, for example, may also promote the neurocrine serotonergic stimulation of growth of colon carcinoma. It is conceivable that colorectal or other gastrointestinal tumors are unique outside of the brain in their ability to co-opt neurocrine serotonin to promote their own growth because peripheral serotonergic neurons are restricted to the gut.² Roles of serotonin in individual tumors, particularly those of the gastrointestinal tract, may have to be assessed to choose the most appropriate antitumor agent. It might be advantageous to match receptor agonists/antagonists to each tumor, rather than (or in addition to) globally potentiating all actions of serotonin with a SERT inhibitor. The applicability of these insights to brain tumors, which have a complex relationship to CD8⁺ T cells, is yet to be investigated. Despite these caveats, the new information from the Yang laboratory suggests that a novel serotonergic boost to checkpoint inhibition may soon be available for cancer chemotherapy.