ß3-adrenergic receptor on tumor-infiltrating lymphocytes sustains IFN-?-dependent PD-L1 expression and impairs anti-tumor immunity in a murine model of neuroblastoma

A distinctive feature of neuroblastoma (NB) tumors is their ability to secrete neuroendocrine mediators such as catecholamines, which through ß-adrenergic receptors ligation may influence different signaling pathways in the tumor microenvironment (TME). Here, we aimed to investigate whether the ß3-AR modulation affected the host immune system response to NB tumor. In a murine syngeneic NB model, pharmacological ß3-AR antagonism lead to an immune response reactivation and reduced tumor growth through the involvement of PD-1/PD-L1 signaling axis. Indeed, ß3-AR blockade on tumor infiltrating lymphocytes (TILs) dampened their ability to secrete IFN-? and reduced PD-L1 expression on NB tumor cells, preventing the establishment of an immune suppressive TME. Furthermore, genomic analysis on NB patients showed that high ADRB3 gene expression correlates with poor clinical outcome. Overall, these findings indicate that ß3-AR is able to sustain an immune suppressive TME in NB via PD-1/PD-L1 crosstalk, and suggest that targeting ß-adrenergic signaling in NB could represent a new strategy to overcome immune escape gateway. Overall design: Comparative gene expression profiling analysis of RNA-seq data for NB murine tumors (derived from N2A tumor cells in A/J mice) treated with vehicle or SR59230A