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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 elevate...

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Bibliographic Details
Published in:Cancer immunology research 2018-01, Vol.6 (1), p.98-109
Main Authors: Nissen, Michael D, Sloan, Erica K, Mattarollo, Stephen R
Format: Article
Language:English
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Summary: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. .
ISSN:2326-6066
2326-6074
DOI:10.1158/2326-6066.CIR-17-0401