Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells
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-adrener...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.03082/full |
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| author | Forrest L. Baker Forrest L. Baker Forrest L. Baker Austin B. Bigley Nadia H. Agha Charles R. Pedlar Daniel P. O'Connor Richard A. Bond Catherine M. Bollard Emmanuel Katsanis Emmanuel Katsanis Richard J. Simpson Richard J. Simpson Richard J. Simpson Richard J. Simpson |
| author_facet | Forrest L. Baker Forrest L. Baker Forrest L. Baker Austin B. Bigley Nadia H. Agha Charles R. Pedlar Daniel P. O'Connor Richard A. Bond Catherine M. Bollard Emmanuel Katsanis Emmanuel Katsanis Richard J. Simpson Richard J. Simpson Richard J. Simpson Richard J. Simpson |
| author_sort | Forrest L. Baker |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T19:50:49Z |
| format | Article |
| id | doaj.art-f17dc4ca5b40422c9322f680279a2730 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-23T19:50:49Z |
| publishDate | 2020-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-f17dc4ca5b40422c9322f680279a27302022-12-21T17:33:24ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-01-011010.3389/fimmu.2019.03082497497Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-CellsForrest L. Baker0Forrest L. Baker1Forrest L. Baker2Austin B. Bigley3Nadia H. Agha4Charles R. Pedlar5Daniel P. O'Connor6Richard A. Bond7Catherine M. Bollard8Emmanuel Katsanis9Emmanuel Katsanis10Richard J. Simpson11Richard J. Simpson12Richard J. Simpson13Richard J. Simpson14Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, United StatesDepartment of Nutritional Sciences, University of Arizona, Tucson, AZ, United StatesDepartment of Pediatrics, University of Arizona, Tucson, AZ, United StatesLaboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, United StatesLaboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, United StatesSchool of Sport, Health and Applied Science, St. Mary's University, London, United KingdomLaboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, United StatesDepartment of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, United StatesCenter for Cancer and Immunology Research, Children's National Health System and the George Washington University, Washington, DC, United StatesDepartment of Pediatrics, University of Arizona, Tucson, AZ, United StatesDepartment of Immunobiology, University of Arizona, Tucson, AZ, United StatesLaboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX, United StatesDepartment of Nutritional Sciences, University of Arizona, Tucson, AZ, United StatesDepartment of Pediatrics, University of Arizona, Tucson, AZ, United StatesDepartment of Immunobiology, University of Arizona, Tucson, AZ, United StatesTCR-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.https://www.frontiersin.org/article/10.3389/fimmu.2019.03082/fullexercise immunologybeta-blockersgamma-delta t-cellsexerciseadoptive transfer immunotherapy |
| spellingShingle | Forrest L. Baker Forrest L. Baker Forrest L. Baker Austin B. Bigley Nadia H. Agha Charles R. Pedlar Daniel P. O'Connor Richard A. Bond Catherine M. Bollard Emmanuel Katsanis Emmanuel Katsanis Richard J. Simpson Richard J. Simpson Richard J. Simpson Richard J. Simpson Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells Frontiers in Immunology exercise immunology beta-blockers gamma-delta t-cells exercise adoptive transfer immunotherapy |
| title | Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells |
| title_full | Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells |
| title_fullStr | Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells |
| title_full_unstemmed | Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells |
| title_short | Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells |
| title_sort | systemic β adrenergic receptor activation augments the ex vivo expansion and anti tumor activity of vγ9vδ2 t cells |
| topic | exercise immunology beta-blockers gamma-delta t-cells exercise adoptive transfer immunotherapy |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.03082/full |
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