Michael D Nissen*1, Erica K Sloan2, Stephen R Mattarollo1
1University of Queensland Diamantina Institute, University of Queensland
2Monash Institute of Pharmaceutical Sciences, Monash University; Semel Institute and Jonsson Comprehensive Cancer Center, University of California Los Angeles; Division of Surgery, Peter MacCallum Cancer Centre
Immunotherapies have revolutionized treatment for cancer, including lymphomas. However the effectiveness of immunotherapies remains sub-optimal, for reasons that are not well defined. Beta-adrenergic receptor (bAR) signalling plays a role in regulating physiological homeostasis, and has been shown to modulate the immune system. Therefore bAR signalling could play a role in regulating the response to cancer immunotherapy. We investigated the impact of bAR signalling on lymphoma progression and response to immunotherapy using a non-selective beta-agonist isoprenaline.
Daily injection with isoprenaline showed that bAR stimulation enhanced lymphoma growth and accelerated mortality. bAR signalling reduced the efficacy of an NKT cell-targeting autologous tumor cell vaccine, shown by increased tumor growth and decreased survival of animals treated with vaccine. bAR signalling reduced the efficacy of anti-PD-1 and anti-4-1BB antibody therapies, and CD8+ T cells generated by immunotherapy during bAR signalling failed to protect naïve mice from lymphoma. bAR signalling reduced proliferation and function of CD8+ T cells in response to vaccination. We observed reduced IFNy and TNFa production and reduced cytolytic activity, suggesting a possible mechanism for reduced immunotherapy efficacy.
These findings suggest that bAR signalling causes immunosuppression via multiple deficiencies in CD8+ T cell function, and impairs immunotherapy in a mouse model of lymphoma. We predict from these findings that cancer immunotherapies may have limited efficacy in patients who are experiencing high levels of bAR signalling, such as during times of chronic stress. Future studies will investigate if blocking bAR signalling pathways improves the effect of immunotherapies.
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