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

• Published in: Neuropeptides (Edinburgh) 2021-10, Vol.89, p.102159-102159, Article 102159
• Main Authors: Levite, Mia, Safadi, Rifaat, Milgrom, Yael, Massarwa, Muhammad, Galun, Eithan
• Format: Article
• Language: English
• Subjects: Calcitonin gene-related peptide; CD4 antigen; Cell proliferation; CGRP; Clinical trials; COVID-19; Dopamine; Dopamine receptors; Glutamate; Glutamic acid receptors; Glutamic acid receptors (ionotropic); Glutamic acid receptors (metabotropic); GnRH-II; Gonadotropin-releasing hormone; Hepatocellular carcinoma; Immunotherapy; Inflammation; Liver cancer; Lymphocytes; Lymphocytes T; N-Methyl-D-aspartic acid receptors; Natural killer cells; Nerve-driven immunity; Neuro-Immunotherapy; Neuropeptide receptors; Neuropeptide Y; Neuropeptides; Neurotransmitters; Patients; PD-1; PD-1 protein; T cells; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
• ISSN: 0143-4179; 1532-2785
• DOI: 10.1016/j.npep.2021.102159

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.