Adrenergic receptor signaling regulates the CD40-receptor mediated anti-tumor immunity

InroductionAnti-CD40 agonistic antibody (alpha CD40), an activator of dendritic cells (DC) can enhance antigen presentation and activate cytotoxic T-cells against poorly immunogenic tumors. However, cancer immunotherapy trials also suggest that alpha CD40 is only moderately effective in patients, falling short of achieving clinical success. Identifying factors that decrease alpha CD40 immune-stimulating effects can aid the translation of this agent to clinical reality. Method/ResultsHere, we reveal that beta-adrenergic signaling on DCs directly interferes with alpha CD40 efficacy in immunologically cold head and neck tumor model. We discovered that beta-2 adrenergic receptor (beta 2AR) activation rewires CD40 signaling in DCs by directly inhibiting the phosphorylation of I kappa B alpha and indirectly by upregulating levels of phosphorylated-cAMP response element-binding protein (pCREB). Importantly, the addition of propranolol, a pan beta-Blocker reprograms the CD40 pathways, inducing superior tumor regressions, increased infiltration of cytotoxic T-cells, and a reduced burden of regulatory T-cells in tumors compared to monotherapy. Discussion/ConclusionThus, our study highlights an important mechanistic link between stress-induced beta 2AR signaling and reduced alpha CD40 efficacy in cold tumors, providing a new combinatorial approach to improve clinical outcomes in patients.