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

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