Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells

Abstract

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 β 1-AR antagonist (bisoprolol) and a non-preferential β 1 + β 2-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 β 1 + β 2-AR (nadolol), but not a β 1-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 Baker et al. Systemic β-AR Activation of Vγ9Vδ2 T-Cells TCR-γδ T-cells and that some of these effects are due to β 2-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.

Cancer immunotherapy with γδ T cells: many paths ahead of us

“…In a recent study, it was reported that systemic β-adrenergic receptor activation, which was accomplished by dynamic physical exercise, mobilized γδ T cells to the blood and significantly augmented their subsequent in vitro expansion capacity and cytotoxic antitumor activity. 164 A placebo-controlled crossover study applying adrenergic receptor inhibitors indicated that effects on the γδ T cell compartment were mediated by the β2—rather than the β1 adrenergic receptor. 164 …”

“… 164 A placebo-controlled crossover study applying adrenergic receptor inhibitors indicated that effects on the γδ T cell compartment were mediated by the β2—rather than the β1 adrenergic receptor. 164 …”

Characterization of Donor Variability for γδ T Cell ex vivo Expansion and Development of an Allogeneic γδ T Cell Immunotherapy

“…It is possible that the donor variability observed in this study, as well as others, could be accounted for by variability in the donors' lifestyles. Exercise immediately prior to PBMC isolation has been shown to increase the ex vivo expansion of γδ T cells (42). In this study, a donor's level of exercise was predictive of their γδ T cell expansion potential.…”

Impact of Polypharmacy for Chronic Ailments in Colon Cancer Patients: A Review Focused on Drug Repurposing

“…There is no definitive explanation of the mechanisms that underlie this findings: even though a series of preclinical data have been published on the matter [ 20 , 21 , 22 ], these studies have stopped in the preclinical phase, failing to have some form of validation in the clinical setting.…”