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Neurotransmitters and Neuropeptides decrease PD-1 in T cells of healthy subjects and patients with hepatocellular carcinoma (HCC), and increase their proliferation and eradication of HCC cells.
- Source :
-
Neuropeptides [Neuropeptides] 2021 Oct; Vol. 89, pp. 102159. Date of Electronic Publication: 2021 May 12. - Publication Year :
- 2021
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Abstract
- T cells of aged people, and of patients with either cancer or severe infections (including COVID-19), are often exhausted, senescent and dysfunctional, leading to increased susceptibilities, complications and mortality. Neurotransmitters and Neuropeptides bind their receptors in T cells, and induce multiple beneficial T cell functions. Yet, T cells of different people vary in the expression levels of Neurotransmitter and Neuropeptide receptors, and in the magnitude of the corresponding effects. Therefore, we performed an individual-based study on T cells of 3 healthy subjects, and 3 Hepatocellular Carcinoma (HCC) patients. HCC usually develops due to chronic inflammation. The inflamed liver induces reduction and inhibition of CD4 <superscript>+</superscript> T cells and Natural Killer (NK) cells. Immune-based therapies for HCC are urgently needed. We tested if selected Neurotransmitters and Neuropeptides decrease the key checkpoint protein PD-1 in human T cells, and increase proliferation and killing of HCC cells. First, we confirmed human T cells express all dopamine receptors (DRs), and glutamate receptors (GluRs): AMPA-GluR3, NMDA-R and mGluR. Second, we discovered that either Dopamine, Glutamate, GnRH-II, Neuropeptide Y and/or CGRP (10nM), as well as DR and GluR agonists, induced the following effects: 1. Decreased significantly both %PD-1 <superscript>+</superscript> T cells and PD-1 expression level per cell (up to 60% decrease, within 1 h only); 2. Increased significantly the number of T cells that proliferated in the presence of HCC cells (up to 7 fold increase), 3. Increased significantly T cell killing of HCC cells (up to 2 fold increase). 4. Few non-conventional combinations of Neurotransmitters and Neuropeptides had surprising synergistic beneficial effects. We conclude that Dopamine, Glutamate, GnRH-II, Neuropeptide Y and CGRP, alone or in combinations, can decrease % PD-1 <superscript>+</superscript> T cells and PD-1 expression per cell, in T cells of both healthy subjects and HCC patients, and increase their proliferation in response to HCC cells and killing of HCC cells. Yet, testing T cells of many more cancer patients is absolutely needed. Based on these findings and previous ones, we designed a novel "Personalized Adoptive Neuro-Immunotherapy", calling for validation of safety and efficacy in clinical trials.<br /> (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Subjects :
- CD4-Positive T-Lymphocytes metabolism
COVID-19 complications
Carcinoma, Hepatocellular pathology
Dopamine pharmacology
Dopamine Agonists pharmacology
Humans
Immunotherapy
Killer Cells, Natural metabolism
Liver Neoplasms pathology
Receptors, Glutamate drug effects
Receptors, Neuropeptide metabolism
Receptors, Neurotransmitter metabolism
Carcinoma, Hepatocellular drug therapy
Carcinoma, Hepatocellular metabolism
Cell Proliferation drug effects
Liver Neoplasms drug therapy
Liver Neoplasms metabolism
Neuropeptides pharmacology
Neurotransmitter Agents pharmacology
Programmed Cell Death 1 Receptor biosynthesis
Programmed Cell Death 1 Receptor genetics
T-Lymphocytes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1532-2785
- Volume :
- 89
- Database :
- MEDLINE
- Journal :
- Neuropeptides
- Publication Type :
- Academic Journal
- Accession number :
- 34293596
- Full Text :
- https://doi.org/10.1016/j.npep.2021.102159