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.
Highlights
TCR-γδ T-cells comprise 1–5% of the total peripheral blood Tcell pool and predominantly recognize non-classical MHC class I molecules and unconventional antigens such as phosphorylated microbial metabolites and lipids [1]
We have demonstrated that systemic β-adrenergic receptor (β-AR) activation, using acute dynamic exercise as an experimental model, mobilizes TCR-γδ T-cells to the peripheral blood and, for the first time here, augments their ex vivo expansion and anti-tumor activity
The ex vivo manufacture and adoptive transfer of TCR-γδ T-cells are being applied to elicit graft- vs.-tumor (GvT) effects in allogeneic hematopoietic cell transplantation (alloHCT) recipients and in the treatment of solid tumors such as renal cell carcinoma, melanoma, lung cancer, and neuroblastoma [7]
Summary
TCR-γδ T-cells comprise 1–5% of the total peripheral blood Tcell pool and predominantly recognize non-classical MHC class I molecules and unconventional antigens such as phosphorylated microbial metabolites and lipids [1] They share properties with NK-cells in that they are capable of killing malignant cells in a non-MHC-restricted manner [2, 3] and have emerged as important players in allogeneic hematopoietic cell transplantation (alloHCT) and immune cell therapy. Post-HCT ZOL+IL-2 therapy fails to expand TCR-γδ cells in vivo to levels associated with increased survival in ∼58% of alloHCT patients [9], while the ex vivo expansion of Vγ9Vδ2 with ZOL+IL-2 for adoptive transfer therapy is sometimes unsuccessful due to low numbers of TCR-γδ T-cells in peripheral blood [10]. To find new ways of mobilizing TCR-γδ T-cells to enrich peripheral blood hematopoietic stem cell grafts prior to transplant, and to augment TCR-γδ responses to ZOL+IL-2 both in vivo and ex vivo [9, 11]
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