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 beta-adrenergic receptors ligation, may affect different signaling pathways in tumor microenvironment (TME). It was previously demonstrated that specific antagonism of beta 3-adrenergic receptor (beta 3-AR) on NB tumor cells affected tumor growth and progression. Here, in a murine syngeneic model of NB, we aimed to investigate whether the beta 3-AR modulation influenced the host immune system response against tumor. Results demonstrated that beta 3-AR antagonism lead to an immune response reactivation, partially dependent on the PD-1/PD-L1 signaling axis involvement. Indeed, beta 3-AR blockade on tumor-infiltrating lymphocytes (TILs) dampened their ability to secrete IFN-gamma, 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 beta 3-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.[GRAPHICS].

β3-adrenergic receptor on tumor-infiltrating lymphocytes sustains IFN-γ-dependent PD-L1 expression and impairs anti-tumor immunity in neuroblastoma / Bruno, Gennaro; Nastasi, Nicoletta; Subbiani, Angela; Boaretto, Alessia; Ciullini Mannurita, Sara; Mattei, Gianluca; Nardini, Patrizia; Della Bella, Chiara; Magi, Alberto; Pini, Alessandro; De Marco, Emanuela; Tondo, Annalisa; Favre, Claudio; Calvani, Maura. - In: CANCER GENE THERAPY. - ISSN 0929-1903. - ELETTRONICO. - (2023), pp. 0-0. [10.1038/s41417-023-00599-x]

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

Bruno, Gennaro;Nastasi, Nicoletta;Subbiani, Angela;Boaretto, Alessia;Ciullini Mannurita, Sara;Mattei, Gianluca;Nardini, Patrizia;Della Bella, Chiara;Magi, Alberto;Pini, Alessandro;Favre, Claudio;Calvani, Maura
2023

Abstract

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 beta-adrenergic receptors ligation, may affect different signaling pathways in tumor microenvironment (TME). It was previously demonstrated that specific antagonism of beta 3-adrenergic receptor (beta 3-AR) on NB tumor cells affected tumor growth and progression. Here, in a murine syngeneic model of NB, we aimed to investigate whether the beta 3-AR modulation influenced the host immune system response against tumor. Results demonstrated that beta 3-AR antagonism lead to an immune response reactivation, partially dependent on the PD-1/PD-L1 signaling axis involvement. Indeed, beta 3-AR blockade on tumor-infiltrating lymphocytes (TILs) dampened their ability to secrete IFN-gamma, 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 beta 3-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.[GRAPHICS].
2023
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Bruno, Gennaro; Nastasi, Nicoletta; Subbiani, Angela; Boaretto, Alessia; Ciullini Mannurita, Sara; Mattei, Gianluca; Nardini, Patrizia; Della Bella, Chiara; Magi, Alberto; Pini, Alessandro; De Marco, Emanuela; Tondo, Annalisa; Favre, Claudio; Calvani, Maura
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1302239
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