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posted on 2024-05-13, 14:20 authored by Forrest L. Baker, Kyle A. Smith, Preetesh L. Mylabathula, Tiffany M. Zúñiga, Douglass M. Diak, Helena Batatinha, Grace M. Niemiro, Michael D. Seckeler, Charles R. Pedlar, Daniel P. O'Connor, Jamie Colombo, Emmanuel Katsanis, Richard J. Simpson Systemic β-AR activation through either acute exercise or ISO infusion evoke similar transcriptomic and surface phenotype shifts among ex vivo expanded Vγ9Vδ2+ T-cells. A, The percentage of activating, inhibitory, and chemokine receptors among expanded Vγ9Vδ2+ T-cells before (REST) and during (EX) exercise or ISO infusion. (n = 8). Statistical significance set as *, P < 0.05. GSEA performed using KEGG and GO terms showing enriched pathways on expanded Vγ9Vδ2+ T-cells that were expanded after (B) exercise or (C) ISO infusion. Graphs show enriched upregulated (blue) and downregulated (red) pathways as well as the percentage of DEGs contributing to each mechanism. Statistical significance set as FDR ≤ 0.25. Data are represented as mean.
Funding
HHS | NIH | National Cancer Institute (NCI)
American College of Sports Medicine (ACSM)
University of Arizona Cancer Center (UACC)
People Acting Now Discover Awards (PANDA)
HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
History
ARTICLE ABSTRACT
Exercise mobilizes cytotoxic lymphocytes to blood which may allow superior cell products to be harvested and manufactured for cancer therapy. Gamma-Delta (γδ) 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 γδ 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 IL2, exercise mobilized γδ 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 β1+β2-agonist isoproterenol and administering β1 or β1+β2 antagonists prior to exercise revealed these effects to be β2-adrenergic receptor (AR) dependent. Antibody blocking of DNAM-1 on expanded γδ T-cells, as well as the DNAM-1 ligands PVR and Nectin-2 on leukemic targets, abolished the enhanced antileukemic effects of exercise. These findings provide a mechanistic link between exercise, β2-AR activation, and the manufacture of superior γδ T-cell products for adoptive cell therapy against hematologic malignancies.
Exercise mobilizes effector γδ T-cells to blood via β2-adrenergic signaling which allows for generation of a potent expanded γδ T-cell product that is highly cytotoxic against hematologic malignancies.
