Attenuation of peripheral serotonin inhibits tumor growth and enhances immune checkpoint blockade therapy in murine tumor models
- 15 September 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 13 (611), eabc8188
- https://doi.org/10.1126/scitranslmed.abc8188
Abstract
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.Keywords
This publication has 72 references indexed in Scilit:
- Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in miceBlood, 2013
- Molecular Mechanisms of SERT in Platelets: Regulation of Plasma Serotonin LevelsMolecular Interventions, 2010
- PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumorsProceedings of the National Academy of Sciences of the United States of America, 2010
- Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosisNature Medicine, 2010
- Peritoneal Colorectal Carcinomatosis Treated With Surgery and Perioperative Intraperitoneal Chemotherapy: Retrospective Analysis of 523 Patients From a Multicentric French StudyJournal of Clinical Oncology, 2010
- Intracellular Serotonin Modulates Insulin Secretion from Pancreatic β-Cells by Protein SerotonylationPLoS Biology, 2009
- Antidepressant use and colorectal cancer riskPharmacoepidemiology and Drug Safety, 2009
- Serotonin: a reviewJournal of Veterinary Pharmacology and Therapeutics, 2008
- Transglutaminase 2 inhibitors and their therapeutic role in disease statesPharmacology & Therapeutics, 2007
- Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptorBlood, 2006