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Exercise-induced beta2 adrenergic receptor activation enhances the anti-leukemic activity of expanded gamma-delta T-Cells via DNAM-1 upregulation and PVR-Nectin-2 recognition

ABSTRACT: Exercise mobilizes cytotoxic lymphocytes to blood which may allow superior cell products to be manufactured for cancer therapy. Gamma-delta T-cells have shown promise for treating solid tumors, but there is a need to increase their potency against hematologic malignancies. Here, we show that human gamma-delta T-cells mobilized to blood in response to just 20-minutes of graded exercise have surface phenotypes and transcriptomic profiles associated with cytotoxicity, adhesion, migration and cytokine signaling. Following 14-days ex vivo expansion with zoledronic acid and interleukin (IL)-2, exercise mobilized gamma-delta T-cells had surface phenotypes and transcriptomic profiles associated with enhanced effector functions, and demonstrated superior cytotoxic activity against multiple hematologic tumors in vitro, and in vivo in leukemia bearing xenogeneic mice. Infusing humans with the beta1+beta2-agonist isoproterenol and administering beta1 or beta1+beta2 antagonists prior to exercise revealed these effects to be beta2-adrenergic receptor (AR) dependent. Antibody blocking of DNAM-1 on expanded gamma-delta T-cells, as well as the DNAM-1 ligands PVR and Nectin-2 on leukemic targets, abolished the enhanced anti-leukemic effects of exercise. These findings provide a mechanistic link between exercise, beta2-AR activation, and the manufacture of superior gamma-delta T-cell products for adoptive cell therapy against hematological malignancies. Expanded Vgamma9Vdelta2+ T-cells expanded, from the same participants, after both exercise (n=2) and isoproterenol infusion (n=2) underwent bulk RNA sequencing and gene expression analysis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263181 | GEO | 2024/04/04

REPOSITORIES: GEO

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Single cell RNA sequencing of murine gamma delta T cells from wild type and beta2 integrin-deficient (CD18 KO) lungs

Project description:The beta2 integrin subunit (CD18) is thought to regulate gamma delta T cells in vivo. The objective of this study was to determine the gene expression changes mediated by loss of CD18 in lung gamma delta T cells. Single cell RNA sequencing was performed on gamma delta T cells (CD3+ gamma delta TCR+) isolated from the lungs of wild type C57BL/6 mice (N=2) and CD18 knockout (Itgb2-/-) mice (N=1).

2020-08-14 | E-MTAB-8732 | biostudies-arrayexpress

Acute effects of Salbutamol in Mouse Kidney Distal Convoluted Tubules (mpkDCT) Cells

Project description:The sympathetic nervous system (SNS) plays a central role in blood pressure regulation. Recent studies have shown that cells of the distal convoluted tubule (DCT) can be stimulated directly via the beta-adrenergic receptor resulting in activation of the NaCl cotransporter NCC. Whether these effects are mediated by the beta1- or beta2-adrenergic receptor is unclear, and the acute signaling cascades rapidly activated by beta-adrenergic receptor stimulation in the DCT are unknown. Here in this study, we aim to identify the rapid salbutamol-mediated (beta2-adrenergic receptor) signaling in the DCT by looking at global protein phosphorylation changes in the mpkDCT cells.

2021-05-17 | PXD019051 | Pride

Acute exercise mobilizes NKT-like cells with a cytotoxic transcriptomic profile but does not augment the potency of cytokine-induced killer (CIK) cells

Project description:CD3+/CD56+ Natural killer (NK) cell-like T-cells (NKT-like cells) represent <5% of blood lymphocytes, display a cytotoxic phenotype, and can kill various cancers. NKT-like cells can be expanded ex vivo into cytokine-induced killer (CIK) cells, however this therapeutic cell product has had mixed results against hematological malignancies in clinical trials. The aim of this study was to determine if NKT-like cells mobilized during acute cycling exercise could be used to generate more potent anti-tumor CIK cells from healthy donors. An acute exercise bout increased NKT-like cell numbers in blood 2-fold. Single cell RNA sequencing revealed that exercise mobilized NKT-like cells have an upregulation of genes and transcriptomic programs associated with enhanced anti-tumor activity, including cytotoxicity, cytokine responsiveness, and migration. Exercise, however, did not augment the ex vivo expansion of CIK cells or alter their surface phenotypes after 21-days of culture. CIK cells expanded at rest, during exercise (at 60% and 80% VO2max) or after (1h post) were equally capable of killing leukemia, lymphoma, and multiple myeloma target cells with and without cytokine (IL-2) and antibody (OKT3) priming in vitro. We conclude that acute exercise in healthy donors mobilizes NKT-like cells with an upregulation of transcriptomic programs involved in anti-tumor activity, but does not augment the ex vivo expansion of CIK cells.

2022-09-12 | GSE212740 | GEO

Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated membrane Beta1/Beta2-integrin expression

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2013-01-30 | GSE43806 | GEO

Transcription profiling of human NK-cell associated receptors expression in EBV-positive gamma-delta T cell lines.

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2009-12-18 | E-GEOD-13906 | biostudies-arrayexpress

NK-cell associated receptors expression in EBV-positive gamma-delta T cell lines.

2009-12-09 | GSE13906 | GEO

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2013-01-30 | E-GEOD-43806 | biostudies-arrayexpress

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2009-11-10 | E-GEOD-18801 | biostudies-arrayexpress

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2008-06-15 | E-GEOD-7144 | biostudies-arrayexpress

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