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.

老年人以及患有癌症或严重感染（包括 COVID-19）的患者的 T 细胞通常会耗尽、衰老和功能失调，导致易感性、并发症和死亡率增加。

神经递质和神经肽结合它们在 T 细胞中的受体，并诱导多种有益的 T 细胞功能。然而，不同人的 T 细胞在神经递质和神经肽受体的表达水平以及相应作用的大小方面有所不同。

因此，我们对 3 名健康受试者和 3 名肝细胞癌 (HCC) 患者的 T 细胞进行了基于个体的研究。HCC 通常由慢性炎症引起。发炎的肝脏会诱导 CD4 ⁺ T 细胞和自然杀伤 (NK) 细胞的减少和抑制。迫切需要针对 HCC 的免疫疗法。

我们测试了选定的神经递质和神经肽是否会降低人类 T 细胞中的关键检查点蛋白 PD-1，并增加 HCC 细胞的增殖和杀伤。

首先，我们证实人类 T 细胞表达所有多巴胺受体 (DR) 和谷氨酸受体 (GluR)：AMPA-GluR3、NMDA-R 和 mGluR。其次，我们发现多巴胺、谷氨酸盐、GnRH-II、神经肽 Y 和/或 CGRP (10nM) 以及 DR 和 GluR 激动剂可诱导以下效应：1 . 显着降低每个细胞的%PD-1 ⁺ T 细胞和 PD-1 表达水平（降低高达 60%，仅在 1 小时内）；2.显着增加在 HCC 细胞存在下增殖的 T 细胞数量（最多增加 7 倍），3.显着增加对 HCC 细胞的 T 细胞杀伤（最多增加 2 倍）。4. 很少有神经递质和神经肽的非常规组合具有令人惊讶的协同有益效果。

我们得出结论，多巴胺、谷氨酸、GnRH-II、神经肽 Y 和 CGRP，单独或组合使用，可以降低健康受试者和 HCC 患者 T 细胞中的PD-1 ⁺ T 细胞百分比和每个细胞的 PD-1 表达，并且增加它们的增殖以响应 HCC 细胞和杀死 HCC 细胞。然而，绝对需要测试更多癌症患者的 T 细胞。

基于这些发现和之前的发现，我们设计了一种新颖的“个性化过继性神经免疫疗法”，呼吁在临床试验中验证安全性和有效性。