Exercise-induced β₂-adrenergic receptor activation enhances effector lymphocyte mobilization in humans and suppresses lymphoma growth in mice through NK-cells

Signaling through the β₂-adrenergic receptor (β2-AR) mobilizes immune cells during exercise and is implicated in tumor lymphocyte infiltration. We investigated mechanisms governing immune cell mobilization in humans and the role of adrenergic signaling in anti-cancer responses to a murine lymphoma. Human studies included double-blind, placebo-controlled, crossover trials with beta blocker drugs and a phosphodiesterase inhibitor during steady-state and graded exercise, and a synthetic β agonist (isoproterenol) infusion model. β₁ + β₂-AR blockade reduced lymphocyte and NK-cell mobilization during steady-state exercise, while β₁-AR blockade enhanced the mobilization of NK-cells. Combining a β₁-AR antagonist with a phosphodiesterase-4 (PDE4) inhibitor during graded exercise further increased mobilization of CD8 + T-cells, γδ T-cells, and monocytes. Isoproterenol infusion also elevated lymphocyte and NK-cell levels similarly to exercise at 70 % VO_2max. Single cell RNA sequencing revealed complex signaling downstream of cAMP that relate to lymphocyte activation and effector function. In murine models of voluntary wheel running, β₂-AR signaling and NK-cells were critical for exercise-induced protection against B-cell lymphoma, as β₂-AR blockade or NK-cell depletion abrogated these effects. These findings highlight the pivotal role of β₂-AR signaling in mobilizing cytotoxic immune cells and protecting against tumor progression through exercise, suggesting potential therapeutic strategies combining exercise with adrenergic modulation to enhance immune responses.