Platelet-derived peripheral serotonin has pleiotropic effects on coagulation, metabolism, tissue regeneration, and cancer growth; however, the effect of serotonin on the tumor microenvironment remains understudied. Peripheral serotonin–deficient (Tph1^−/−) mice displayed reduced growth of subcutaneous and orthotopically injected syngeneic murine pancreatic and colorectal cancers with enhanced accumulation of functional CD8⁺ T cells compared to control C57BL/6 mice, resulting in extended overall survival. Subcutaneous and orthotopic syngeneic tumors from Tph1^−/− mice expressed less programmed cell death 1 ligand 1 (PD-L1), suggesting serotonin-mediated regulation. Serotonin enhanced expression of PD-L1 on mouse and human cancer cells in vitro via serotonylation, which is the formation of covalent bonds between glutamine residues and serotonin, resulting in activation of small G proteins. Serotonin concentrations in metastases of patients with abdominal tumors negatively correlated to the number of CD8⁺ tumor-infiltrating T cells. Depletion of serotonin cargo or inhibition of serotonin release from thrombocytes decreased growth of syngeneic pancreatic and colorectal tumors in wild-type mice, increased CD8⁺ T cell influx, and decreased PD-L1 expression. Pharmacological serotonin depletion with oral fluoxetine or intraperitoneal injection of the TPH1 inhibitor telotristat augmented the effects of programmed cell death protein 1 (PD-1) checkpoint blockade and triggered long-term tumor control in mice subcutaneously inoculated with syngeneic colorectal and pancreatic tumors. Overall, peripheral serotonin weakens effector functions of CD8⁺ T cells within tumors. Clinically approved serotonin targeting agents alone or in combination with PD-1 blockade provided long-term control of established tumors in murine models, warranting further investigation of the clinical translatability of these findings.

中文翻译：

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外周血清素的减弱抑制肿瘤生长并增强小鼠肿瘤模型中的免疫检查点阻断治疗

血小板衍生的外周血清素对凝血、代谢、组织再生和癌症生长具有多效性；然而，血清素对肿瘤微环境的影响仍未得到充分研究。与对照 C57BL/6 小鼠相比，外周血清素缺乏 ( Tph1 ^-/- ) 小鼠的皮下和原位注射的同系小鼠胰腺癌和结肠直肠癌的生长减少，功能性 CD8 ^{+ T 细胞的积累增加，从而延长了总生存期。}来自Tph1的皮下和原位同系肿瘤^-/-小鼠表达较少的程序性细胞死亡 1 配体 1 (PD-L1)，表明血清素介导的调节。血清素通过血清素化增强小鼠和人类癌细胞体外 PD-L1 的表达，血清素化是谷氨酰胺残基和血清素之间形成共价键，导致小 G 蛋白活化。腹部肿瘤患者转移灶中的血清素浓度与 CD8 ⁺肿瘤浸润性 T 细胞的数量呈负相关。血清素货物的消耗或血清素从血小板释放的抑制降低了野生型小鼠同基因胰腺和结肠直肠肿瘤的生长，增加了 CD8 ⁺T 细胞流入，PD-L1 表达降低。口服氟西汀或腹膜内注射 TPH1 抑制剂 telotristat 的药理学血清素消耗增强了程序性细胞死亡蛋白 1 (PD-1) 检查点阻断的作用，并在皮下接种同基因结直肠和胰腺肿瘤的小鼠中触发了长期肿瘤控制。总体而言，外周血清素会削弱肿瘤内 CD8 ⁺ T 细胞的效应功能。临床批准的血清素靶向剂单独或与 PD-1 阻断剂联合使用可长期控制小鼠模型中已建立的肿瘤，值得进一步研究这些发现的临床可转化性。