Science子刊:靶向抑制5-羟色胺或可增强PD-1单抗的疗效
创作:aluba 审核:aluba 2021年10月04日
  • 在胰腺癌及结直肠癌的皮下及原位接种小鼠模型中,敲除Tph1减少肿瘤生长,增加功能性CD8+ T细胞瘤内累积,以延长总生存期;
  • Tph1敲除小鼠的PD-L1表达降低,5羟色胺通过serotonylation修饰激活小G蛋白,以上调PD-L1表达;
  • 在腹部肿瘤腹膜转移患者中,瘤内的5羟色胺浓度与CD8+ T细胞浸润呈负相关,与PD-L1的表达呈正相关;
  • 在结直肠癌及胰腺癌的皮下接种小鼠模型中,口服氟西汀或腹膜内注射TPH1抑制剂telotristat可增强PD-1单抗的疗效。
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aluba
血小板产生的外周5羟色胺在肿瘤微环境中的作用尚未明确。Science Translational Medicine上发表的一项最新研究,发现敲除色氨酸羟化酶1(TPH1,5羟色胺合成的限速酶)以抑制小鼠的外周5羟色胺产生,可抑制胰腺癌及结直肠癌的皮下及原位接种模型的肿瘤生长。机制上,5羟色胺可通过serotonylation修饰(谷氨酰胺与5羟色胺之间形成的共价键)增加PD-L1的表达。抑制血小板的5羟色胺摄取及储存(氟西汀)或抑制TPH1活性(telotristat)可在胰腺癌及结直肠癌的皮下接种小鼠模型中,增强PD-1单抗的治疗效果。
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Attenuation of peripheral serotonin inhibits tumor growth and enhances immune checkpoint blockade therapy in murine tumor models

在小鼠肿瘤模型中,抑制外周的5羟色胺可抑制肿瘤生长并增强免疫检查点抑制剂的疗效

10.1126/scitranslmed.abc8188

2021-09-15, Article

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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.

First Authors:
Marcel André Schneider

Correspondence Authors:
Anurag Gupta,Pierre-Alain Clavien

All Authors:
Marcel André Schneider,Laura Heeb,Michal Mateusz Beffinger,Stanislav Pantelyushin,Michael Linecker,Lilian Roth,Kuno Lehmann,Udo Ungethüm,Sebastian Kobold,Rolf Graf,Maries van den Broek,Johannes vom Berg,Anurag Gupta,Pierre-Alain Clavien

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