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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.
Neuropeptides. 2021 Oct; 89:102159.N

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+ 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+ 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+ 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.

Authors+Show Affiliations

Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel; Institute of Gene Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem 91120, Israel. Electronic address: mialevite@mta.ac.il.The Liver Unit, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem 91120, Israel.The Liver Unit, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem 91120, Israel.The Liver Unit, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem 91120, Israel.Institute of Gene Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem 91120, Israel.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34293596

Citation

Levite, Mia, et al. "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." Neuropeptides, vol. 89, 2021, p. 102159.
Levite M, Safadi R, Milgrom Y, et al. 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. Neuropeptides. 2021;89:102159.
Levite, M., Safadi, R., Milgrom, Y., Massarwa, M., & Galun, E. (2021). 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. Neuropeptides, 89, 102159. https://doi.org/10.1016/j.npep.2021.102159
Levite M, et al. 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. Neuropeptides. 2021;89:102159. PubMed PMID: 34293596.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Levite,Mia, AU - Safadi,Rifaat, AU - Milgrom,Yael, AU - Massarwa,Muhammad, AU - Galun,Eithan, Y1 - 2021/05/12/ PY - 2021/03/01/received PY - 2021/05/04/revised PY - 2021/05/09/accepted PY - 2021/7/23/pubmed PY - 2021/9/9/medline PY - 2021/7/22/entrez KW - CGRP KW - Dopamine KW - Glutamate KW - GnRH-II KW - Hepatocellular carcinoma KW - Nerve-driven immunity KW - Neuro-Immunotherapy KW - Neuropeptide Y KW - PD-1 KW - T cells SP - 102159 EP - 102159 JF - Neuropeptides JO - Neuropeptides VL - 89 N2 - 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+ 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+ 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+ 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. SN - 1532-2785 UR - https://www.unboundmedicine.com/medline/citation/34293596/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. L2 - https://linkinghub.elsevier.com/retrieve/pii/S0143-4179(21)00045-7 DB - PRIME DP - Unbound Medicine ER -