TCR-gamma delta (γδ) T-cells are considered important players in the graft-vs.-tumor effect following allogeneic hematopoietic cell transplantation (alloHCT) and have emerged as candidates for adoptive transfer immunotherapy in the treatment of both solid and hematological tumors. Systemic β-adrenergic receptor (β-AR) activation has been shown to mobilize TCR-γδ T-cells to the blood, potentially serving as an adjuvant for alloHCT and TCR-γδ T-cell therapy. We investigated if systemic β-AR activation, using acute dynamic exercise as an experimental model, can increase the mobilization, ex vivo expansion, and anti-tumor activity of TCR-γδ T-cells isolated from the blood of healthy humans. We also sought to investigate the β-AR subtypes involved, by administering a preferential β1-AR antagonist (bisoprolol) and a non-preferential β1 + β2-AR antagonist (nadolol) prior to exercise as part of a randomized placebo controlled cross-over experiment. We found that exercise mobilized TCR-γδ cells to blood and augmented their ex vivo expansion by ~182% compared to resting blood when stimulated with IL-2 and ZOL for 14-days. Exercise also increased the proportion of CD56+, NKG2D+/CD62L-, CD158a/b/e+ and NKG2A- cells among the expanded TCR-γδ cells, and increased their cytotoxic activity against several tumor target cells (K562, U266, 221.AEH) in vitro by 40-60%. Blocking NKG2D on TCR-γδ cells in vitro eliminated the augmented cytotoxic effects of exercise against U266 target cells. Furthermore, administering a β1 + β2-AR (nadolol), but not a β1-AR (bisoprolol) antagonist prior to exercise abrogated the exercise-induced enhancement in TCR-γδ T-cell mobilization and ex vivo expansion. Furthermore, nadolol completely abrogated while bisoprolol partially inhibited the exercise-induced increase in the cytotoxic activity of the expanded TCR-γδ T-cells. We conclude that acute systemic β-AR activation in healthy donors markedly augments the mobilization, ex vivo expansion, and anti-tumor activity of TCR-γδ T-cells and that some of these effects are due to β2-AR signaling and phenotypic shifts that promote a dominant activating signal via NKG2D. These findings highlight β-ARs as potential targets to favorably alter the composition of allogeneic peripheral blood stem cell grafts and improve the potency of TCR-γδ T-cell immune cell therapeutics.

中文翻译：

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全身 β-肾上腺素能受体激活增强 Vγ9Vδ2 T 细胞的离体扩增和抗肿瘤活性。


TCR-γδ（γδ）T 细胞被认为是同种异体造血细胞移植（alloHCT）后移植物抗肿瘤效应中的重要参与者，并已成为实体瘤和血液肿瘤治疗中过继转移免疫疗法的候选者。全身 β-肾上腺素能受体 (β-AR) 激活已被证明可以将 TCR-γδ T 细胞动员到血液中，可能作为 alloHCT 和 TCR-γδ T 细胞治疗的佐剂。我们使用急性动态运动作为实验模型，研究了全身 β-AR 激活是否可以增加从健康人血液中分离的 TCR-γδ T 细胞的动员、离体扩增和抗肿瘤活性。我们还试图通过在运动前给予优先的 β1-AR 拮抗剂（比索洛尔）和非优先的 β1 + β2-AR 拮抗剂（纳多洛尔）来研究所涉及的 β-AR 亚型，作为随机安慰剂对照交叉的一部分实验。我们发现，当用 IL-2 和 ZOL 刺激 14 天时，运动将 TCR-γδ 细胞动员到血液中，与静息血液相比，其离体扩增增加约 182%。运动还增加了扩增的TCR-γδ细胞中CD56+、NKG2D+/CD62L-、CD158a/b/e+和NKG2A-细胞的比例，并增加了它们对多种肿瘤靶细胞（K562、U266、221.AEH）的细胞毒活性。体外40-60%。体外阻断 TCR-γδ 细胞上的 NKG2D 可以消除运动对 U266 靶细胞增强的细胞毒性作用。此外，运动前给予 β1 + β2-AR（纳多洛尔）而非 β1-AR（比索洛尔）拮抗剂可消除运动诱导的 TCR-γδ T 细胞动员和离体扩增的增强。 此外，纳多洛尔完全消除，而比索洛尔部分抑制运动诱导的扩增 TCR-γδ T 细胞的细胞毒活性增加。我们得出的结论是，健康供体中急性全身性 β-AR 激活显着增强了 TCR-γδ T 细胞的动员、离体扩增和抗肿瘤活性，其中一些效应是由于 β2-AR 信号传导和表型转变所致。通过 NKG2D 促进显性激活信号。这些发现强调 β-AR 作为潜在靶点，可以有利地改变同种异体外周血干细胞移植物的组成，并提高 TCR-γδ T 细胞免疫细胞疗法的效力。