Serotonin transporter inhibits antitumor immunity through regulating the intratumoral serotonin axis

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2025-05-21 DOI:10.1016/j.cell.2025.04.032

Bo Li, James Elsten-Brown, Miao Li, Enbo Zhu, Zhe Li, Yuning Chen, Elliot Kang, Feiyang Ma, Jennifer Chiang, Yan-Ruide Li, Yichen Zhu, Jie Huang, Audrey Fung, Quentin Scarborough, Robin Cadd, Jin J. Zhou, Arnold I. Chin, Matteo Pellegrini, Lili Yang

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引用次数: 0

Abstract

Identifying additional immune checkpoints hindering antitumor T cell responses is key to the development of next-generation cancer immunotherapies. Here, we report the induction of serotonin transporter (SERT), a regulator 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 widely prescribed antidepressants, significantly suppressed tumor growth and enhanced T cell antitumor immunity in 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 by depleting intratumoral T cell-autocrine serotonin. These findings highlight the significance of the intratumoral serotonin axis and identify SERT as an immune checkpoint, positioning SSRIs as promising candidates for cancer immunotherapy.

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血清素转运体通过调节肿瘤内血清素轴抑制抗肿瘤免疫

识别阻碍抗肿瘤T细胞反应的额外免疫检查点是开发下一代癌症免疫疗法的关键。在这里，我们报道了在肿瘤浸润的CD8 T细胞中诱导血清素转运体（SERT），血清素转运体是大脑和外周组织中血清素水平和生理功能的调节剂。选择性5 -羟色胺再摄取抑制剂（SSRIs）是最常用的抗抑郁药物，在多种小鼠和人类异种移植肿瘤模型中，使用选择性5 -羟色胺再摄取抑制剂（SSRIs）抑制SERT可显著抑制肿瘤生长并增强T细胞抗肿瘤免疫。重要的是，SSRI治疗与程序性细胞死亡蛋白1 （PD-1）阻断表现出显著的治疗协同作用，临床数据相关研究表明，在一系列癌症中，肿瘤内SERT表达与患者生存率呈负相关。从机制上讲，SERT作为一种负反馈调节剂，通过消耗肿瘤内T细胞自分泌血清素来抑制CD8 T细胞的反应性。这些发现强调了肿瘤内血清素轴的重要性，并确定了SERT作为免疫检查点，将SSRIs定位为癌症免疫治疗的有希望的候选者。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.