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

β-Adrenergic receptor (βAR) signaling regulates many physiological processes, including immune system responses. There is growing evidence also for βAR-induced modulation of cancer growth and metastasis. In the Eμ-myc mouse model of B-cell lymphoma, we investigated the effects of chronically elevated βAR signaling on lymphoma progression and antitumor immunity, as well as the impact on cancer immunotherapy. Chronic treatment with the nonselective β-agonist isoprenaline promoted lymphoma development in a manner dependent on signaling within the hematopoietic compartment. βAR signaling significantly suppressed the proliferation, IFNγ 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 stimulation. The suppressive effects of chronic βAR signaling on antitumor 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 βAR signaling has an immunosuppressive effect on CD8⁺ T cells, which decreases the efficacy of CD8⁺ T cell-targeting immunotherapies. These findings identify βAR signaling as a target for modulation during cancer immunotherapy that may increase therapeutic response and improve patient outcomes. Cancer Immunol Res; 6(1); 98-109. ©2017 AACR.