β-Adrenergic Signaling Impairs Antitumor CD8+ T-cell Responses to B-cell Lymphoma Immunotherapy

Beta-adrenergic receptor (betaAR) signaling regulates many physiological processes, including immune system responses. There is growing evidence also for betaAR-induced modulation of cancer growth and metastasis. In the Eu-myc mouse model of B-cell lymphoma, we investigated the effects of chronically elevated betaAR signaling on lymphoma progression and anti-tumor immunity, as well as the impact on cancer immunotherapy. Chronic treatment with the non-selective beta-agonist isoprenaline promoted lymphoma development in a manner dependent on signaling within the hematopoietic compartment. betaAR signaling significantly suppressed the proliferation, IFNgamma production and cytolytic killing capacity of antigen-specific CD8+ T cells. This inhibited CD8+ T-cell responses to immune modulating antibodies, including anti-PD-1 and anti-4-1BB, resulting in less effective control of lymphoma. The inhibitory effects on CD8+ T cells occurred independently of changes to DC function, and included direct suppression of CD8+ T-cell timulation. The suppressive effects of chronic betaAR signaling on anti-tumor effector cells was selective to T cells, as it did not perturb the innate lymphocyte response to an experimental NKT cell-targeting vaccine, in a setting where innate immune control is dependent on NKT cell and NK cell activation. These findings demonstrate that chronic betaAR signaling has an immunosuppressive effect on CD8+ T cells, which decreases the efficacy of CD8+ T cell-targeting immunotherapies. These findings identify betaAR signaling as a target for modulation during cancer immunotherapy that may increase therapeutic response and improve patient outcomes.