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, 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 β-AR antagonist (bisoprolol) and a non-preferential β + β-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 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) by 40-60%. Blocking NKG2D on TCR-γδ cells eliminated the augmented cytotoxic effects of exercise against U266 target cells. Furthermore, administering a β + β-AR (nadolol), but not a β-AR (bisoprolol) antagonist prior to exercise abrogated the exercise-induced enhancement in TCR-γδ T-cell mobilization and 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, expansion, and anti-tumor activity of TCR-γδ T-cells and that some of these effects are due to β-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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993603PMC
http://dx.doi.org/10.3389/fimmu.2019.03082DOI Listing

Publication Analysis

Top Keywords

tcr-γδ t-cells
16
expansion anti-tumor
12
anti-tumor activity
12
β-ar activation
12
tcr-γδ t-cell
12
mobilization expansion
12
tcr-γδ cells
12
tcr-γδ
10
β-ar
9
systemic β-adrenergic
8

Similar Publications

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges.

View Article and Find Full Text PDF

Lipid nanoparticles deliver DNA-encoded biologics and induce potent protective immunity.

Mol Cancer

January 2025

Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.

Lipid nanoparticles (LNPs) for mRNA delivery have advanced significantly, but LNP-mediated DNA delivery still faces clinical challenges. This study compared various LNP formulations for delivering DNA-encoded biologics, assessing their expression efficacy and the protective immunity generated by LNP-encapsulated DNA in different models. The LNP formulation used in Moderna's Spikevax mRNA vaccine (LNP-M) demonstrated a stable nanoparticle structure, high expression efficiency, and low toxicity.

View Article and Find Full Text PDF

Targeting lipid metabolism: novel insights and therapeutic advances in pancreatic cancer treatment.

Lipids Health Dis

January 2025

Emergency surgery Dapartment (Trauma center), The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471003, Henan, China.

Lipid metabolism in cancer is characterized by dysregulated lipid regulation and utilization, critical for promoting tumor growth, survival, and resistance to therapy. Pancreatic cancer (PC) is a highly aggressive malignancy of the gastrointestinal tract that has a dismal 5-year survival rate of less than 10%. Given the essential function of the pancreas in digestion, cancer progression severely disrupts its function.

View Article and Find Full Text PDF

The prognostic value of systemic immune-inflammation index in patients with unresectable hepatocellular carcinoma treated with immune-based therapy.

Biomark Res

January 2025

Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University180 Fenglin Road, Shanghai, 200032, China.

Background: Predicting the efficacy of immune-based therapy in patients with unresectable hepatocellular carcinoma (HCC) remains a clinical challenge. This study aims to evaluate the prognostic value of the systemic immune-inflammation index (SII) in forecasting treatment response and survival outcomes for HCC patients undergoing immune-based therapy.

Methods: We analyzed a cohort of 268 HCC patients treated with immune-based therapy from January 2019 to March 2023.

View Article and Find Full Text PDF

RNA-Targeting CRISPR/CasRx system relieves disease symptoms in Huntington's disease models.

Mol Neurodegener

January 2025

Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), School of Medicine, GHM Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China.

Background: HD is a devastating neurodegenerative disorder caused by the expansion of CAG repeats in the HTT. Silencing the expression of mutated proteins is a therapeutic direction to rescue HD patients, and recent advances in gene editing technology such as CRISPR/CasRx have opened up new avenues for therapeutic intervention.

Methods: The CRISPR/CasRx system was employed to target human HTT exon 1, resulting in an efficient knockdown of HTT mRNA.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!