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

Forrest L. Baker, Austin B. Bigley, Nadia H. Agha, Charles R. Pedlar, Daniel P. O'Connor, Richard A. Bond, Catherine M. Bollard, Emmanuel Katsanis, Richard J. Simpson

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Article number3082
JournalFrontiers in immunology
Volume10
DOIs
StatePublished - Jan 24 2020

Keywords

  • adoptive transfer immunotherapy
  • beta-blockers
  • exercise
  • exercise immunology
  • gamma-delta t-cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells'. Together they form a unique fingerprint.

  • Cite this

    Baker, F. L., Bigley, A. B., Agha, N. H., Pedlar, C. R., O'Connor, D. P., Bond, R. A., Bollard, C. M., Katsanis, E., & Simpson, R. J. (2020). Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells. Frontiers in immunology, 10, [3082]. https://doi.org/10.3389/fimmu.2019.03082