免疫系统在控制上皮卵巢癌（EOC）中扮演重要角色。EOC被认为是一种“冷肿瘤”，即免疫系统没有触发强烈反应的肿瘤。然而，肿瘤浸润淋巴细胞（TILs）和程序性细胞死亡配体（PD-L1）的表达在EOC中被用作预后指标。PD-(L)1抑制剂等免疫疗法在EOC中显示出有限的益处。由于行为压力和β-肾上腺素信号通路影响免疫系统，本研究旨在探索β-受体阻滞剂普萘洛尔（PRO）对于体外和体内EOC模型中的抗肿瘤免疫的影响。肾上腺素能激动剂去甲肾上腺素（NA）没有直接调节PD-L1的表达，但是IFN-γ在EOC细胞系上显着上调PD-L1。IFN-γ还增加了ID8细胞释放的细胞外囊泡（EVs）上的PD-L1的表达。PRO显著降低了原代免疫细胞的体外激活后IFN-γ水平，并在EV-免疫细胞共培养中显示出CD8+细胞种群的增加存活率。此外，PRO在免疫癌细胞共培养中逆转了PD-L1上调并显著降低了IL-10水平。慢性行为应激增加了小鼠的转移，而PRO单药治疗和PRO和PD-(L)1抑制剂的组合显着降低了压力诱导的转移。联合治疗还降低了肿瘤重量，与癌症对照组相比，在肿瘤组织中诱导了抗肿瘤T细胞反应，且CD8表达显著。总之，PRO通过降低IFN-γ的产生以及IFN-γ介导的PD-L1过度表达来调节癌症免疫反应。PRO和PD-(L)1抑制剂的联合疗法降低了转移并改善了抗肿瘤免疫，为一种有前途的新疗法。版权所有©2023作者。由Elsevier Inc. 出版。保留所有权利。

The immune system plays an important role in controlling epithelial ovarian cancer (EOC). EOC is considered to be a "cold tumour," a tumour that has not triggered a strong response by the immune system. However, tumour infiltrating lymphocytes (TILs) and the expression of programmed cell death ligand (PD-L1) are used as prognostic indicators in EOC. Immunotherapy such as PD-(L)1 inhibitors have shown limited benefit in EOC. Since the immune system is affected by behavioural stress and the beta-adrenergic signalling pathway, this study aimed to explore the impact of propranolol (PRO), a beta-blocker, on anti-tumour immunity in both in vitro and in vivo EOC models. Noradrenaline (NA), an adrenergic agonist, did not directly regulate PD-L1 expression but PD-L1 was significantly upregulated by IFN-γ in EOC cell lines. IFN-γ also increased PD-L1 on extracellular vesicles (EVs) released by ID8 cells. PRO significantly decreased IFN-γ levels in primary immune cells activated ex vivo and showed increased viability of the CD8+ cell population in an EV-immune cell co-incubation. In addition, PRO reverted PD-L1 upregulation and significantly decreased IL-10 levels in an immune-cancer cell co-culture. Chronic behavioural stress increased metastasis in mice while PRO monotherapy and the combo of PRO and PD-(L)1 inhibitor significantly decreased stress-induced metastasis. The combined therapy also reduced tumour weight compared to the cancer control group and induced anti-tumour T-cell responses with significant CD8 expression in tumour tissues. In conclusion, PRO showed a modulation of the cancer immune response by decreasing IFN-γ production and, in turn, IFN-γ-mediated PD-L1 overexpression. The combined therapy of PRO and PD-(L)1 inhibitor decreased metastasis and improved anti-tumour immunity offering a promising new therapy.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.