神经母细胞瘤（NB）是一种儿童期发生的异质性颅外肿瘤。NB肿瘤的一种特殊特征是它们的神经内分泌能力，可以分泌儿茶酚胺，而这些激素通过β肾上腺素能受体的结合转导到肿瘤微环境（TME）中的不同信号通路中。之前曾证明特异性β3-肾上腺素能受体（β3-AR）的拮抗剂对NB肿瘤细胞影响了肿瘤生长和进展。在这里，我们研究了β3-AR调节对小鼠同种移植模型中宿主免疫反应对肿瘤的影响。结果表明，β3-AR拮抗剂导致免疫反应重新激活，并部分依赖于PD-1 / PD-L1信号通路的参与。实际上，肿瘤浸润淋巴细胞（TILs）上的β3-AR阻断会减弱它们分泌IFN-γ的能力，从而减少由TILs浸润引起的NB肿瘤细胞PD-L1表达。通过对NB患者的基因组分析进一步研究表明，高ADRB3基因表达与低表达组相比相关性更差的临床结果，并且ADRB3基因表达影响不同的免疫相关途径。总的来说，结果表明NB TME中的β3-AR能够调节肿瘤与宿主免疫系统之间的相互作用，并且其拮抗影响多个促肿瘤信号通路。 © 2023年作者。

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.© 2023. The Author(s).