Journal Article

β3-adrenergic receptor on tumor-infiltrating lymphocytes sustains IFN-γ-dependent PD-L1 expression and impairs anti-tumor immunity in neuroblastoma

Nastasi, Nicoletta, Subbiani, Angela, Della Bella, Chiara, Favre, Claudio, Magi, Alberto, Pini, Alessandro, Bruno, Gennaro, Ciullini Mannurita, Sara, Calvani, Maura, De Marco, Emanuela, Tondo, Annalisa, Mattei, Gianluca, Nardini, Patrizia, Boaretto, Alessia

2023

Overview

Neuroblastoma (NB) is a heterogeneous extracranial tumor occurring in childhood. A distinctive feature of NB tumors is their neuroendocrine ability to secrete catecholamines, which in turn, via β-adrenergic receptors ligation, may affect different signaling pathways in tumor microenvironment (TME). It was previously demonstrated that specific antagonism of β3-adrenergic receptor (β3-AR) on NB tumor cells affected tumor growth and progression. Here, in a murine syngeneic model of NB, we aimed to investigate whether the β3-AR modulation influenced the host immune system response against tumor. Results demonstrated that β3-AR antagonism lead to an immune response reactivation, partially dependent on the PD-1/PD-L1 signaling axis involvement. Indeed, β3-AR blockade on tumor-infiltrating lymphocytes (TILs) dampened their ability to secrete IFN-γ, which in turn reduced the PD-L1 expression, caused by TILs infiltration, on NB tumor cells. Further investigations, through a genomic analysis on NB patients, showed that high ADRB3 gene expression correlates with worse clinical outcome compared to the low expression group, and that ADRB3 gene expression affects different immune-related pathways. Overall, results indicate that β3-AR in NB TME is able to modulate the interaction between tumor and host immune system, and that its antagonism hits multiple pro-tumoral signaling pathways.

• Publisher: Nature Publishing Group
• Subject: Adrenergic receptors / Catecholamines / Children / Clinical outcomes / Gene expression / Genomic analysis / Heterogeneity / Immune response / Immune system / Lymphocytes / Metastases / Neuroblastoma / PD-1 protein / PD-L1 protein / Signal transduction / Tumor cells / Tumor microenvironment / Tumor-infiltrating lymphocytes / γ-Interferon