Zhang Yu, Yu Feng, Ouyang Jing, Liu Panpan, Dai Yingying, Wang Yang, Yi Hanying, Wang Shiyu, Liu Dongbo, Song Kun, Pei Wenwu, Hong Ziyang, Zhang Wei, Huang Weihua, Zhou Gan, Cao Shan, McLeod Howard, Peng Cong, Chen Ling, He Yijing
Department of Clinical Pharmacology, Xiangya Hospital Central South University, Changsha, Hunan, China.
Department of Gastrointestinal Surgery, Xiangya Hospital Central South University, Changsha, Hunan, China.
J Immunother Cancer. 2025 Jun 12;13(6):e011611. doi: 10.1136/jitc-2025-011611.
BACKGROUND: Chronic stress is known to promote cancer progression, in part by modulating immune responses through the β-adrenergic receptor (ADRB2). Inhibiting ADRB2 with β-blockers has demonstrated potential in boosting the effectiveness of immune checkpoint inhibitors across a spectrum of cancers, yet the precise mechanisms remain to be fully elucidated. METHODS: In vivo and in vitro experiments were performed to evaluate the role of ADRB2 in melanoma models, including its effects on T cells. RNA sequencing analysis highlighted the importance of the transcription factor SRY-related HMG-box 10 (SOX10), which transcriptionally regulates programmed death-ligand 1 (PD-L1). This regulatory role was further validated using luciferase reporter assays and chromatin immunoprecipitation-PCR assays. Mechanistic studies focused on ADRB2 signaling through protein kinase A (PKA) and its downstream target SOX10. To investigate SOX10's role in mediating the effects of ADRB2, knockdown and overexpression experiments were conducted. Additionally, similar studies in colorectal cancer (CRC) models confirmed the conserved function of the ADRB2-SOX10-PD-L1 axis. RESULTS: This study explores the role of ADRB2 in regulating tumor PD-L1 expression and T cell functionality, offering insights for cancer immunotherapy. Clinical data revealed that patients with melanoma with high ADRB2 expression responded better to programmed cell death protein 1 inhibitors. In melanoma models, ADRB2 inhibition reduced PD-L1 expression, enhanced T cell infiltration, and promoted antitumor immunity, while ADRB2 activation had the opposite effect. Mechanistically, ADRB2 signaling through PKA upregulated SOX10, which transcriptionally modulates PD-L1. SOX10 knockdown replicated the effects of ADRB2 inhibition, while SOX10 overexpression reversed them. Similar findings in CRC models confirmed the conserved role of the ADRB2-SOX10-PD-L1 axis. Targeting ADRB2 and SOX10 may enhance immune checkpoint inhibitor efficacy in cancer treatment. CONCLUSIONS: These findings underscore the potential of ADRB2 and SOX10 as therapeutic targets for mitigating stress-induced immunosuppression and for augmenting the effectiveness of immunotherapies in a variety of cancer types.
背景：已知慢性应激会促进癌症进展，部分原因是通过β-肾上腺素能受体（ADRB2）调节免疫反应。用β受体阻滞剂抑制ADRB2已显示出在提高免疫检查点抑制剂对多种癌症疗效方面的潜力，但其确切机制仍有待充分阐明。 方法：进行体内和体外实验以评估ADRB2在黑色素瘤模型中的作用，包括其对T细胞的影响。RNA测序分析突出了转录因子SRY相关高迁移率族盒10（SOX10）的重要性，该因子转录调控程序性死亡配体1（PD-L1）。使用荧光素酶报告基因检测和染色质免疫沉淀-PCR检测进一步验证了这种调控作用。机制研究聚焦于ADRB2通过蛋白激酶A（PKA）及其下游靶点SOX10的信号传导。为研究SOX10在介导ADRB2作用中的作用，进行了敲低和过表达实验。此外，在结直肠癌（CRC）模型中的类似研究证实了ADRB2-SOX10-PD-L1轴的保守功能。 结果：本研究探讨了ADRB2在调节肿瘤PD-L1表达和T细胞功能方面的作用，为癌症免疫治疗提供了见解。临床数据显示，ADRB2高表达的黑色素瘤患者对程序性细胞死亡蛋白1抑制剂反应更好。在黑色素瘤模型中；ADRB2抑制降低了PD-L1表达，增强了T细胞浸润，并促进了抗肿瘤免疫，而ADRB2激活则产生相反效果。从机制上讲，ADRB2通过PKA的信号传导上调了SOX10，后者转录调节PD-L1。SOX10敲低复制了ADRB2抑制的效果，而SOX10过表达则逆转了这些效果。CRC模型中的类似发现证实了ADRB2-SOX10-PD-L1轴的保守作用。靶向ADRB2和SOX10可能增强癌症治疗中免疫检查点抑制剂的疗效。 结论：这些发现强调了ADRB2和SOX10作为治疗靶点的潜力，可减轻应激诱导的免疫抑制，并增强多种癌症类型免疫治疗的有效性。
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