Li Qun, Xu Shuning, Ren Yulin, Zhang Cheng, Li Ke, Liu Ying
Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.
Front Immunol. 2025 May 8;16:1520766. doi: 10.3389/fimmu.2025.1520766. eCollection 2025.
Esophageal squamous cell carcinoma (ESCC) presents significant health challenges due to its aggressive nature and poor prognosis from late-stage diagnosis. Despite these challenges, emerging therapies like immune checkpoint inhibitors offer hope. β1-adrenergic signaling has been implicated in T cell exhaustion, which weakens the immune response in ESCC. Blocking this pathway could restore T cell function. Recent advances in single-cell RNA sequencing (scRNA-seq) have enabled deeper insights into tumor heterogeneity and the immune landscape, opening the door for personalized treatment strategies that may improve survival and reduce resistance to therapy.
We combined scRNA-seq with bulk RNA analysis to explore adrenergic receptor signaling in ESCC, focusing on changes before and after neoadjuvant therapy. We identified ADRB1 T cells through data analysis and experimental validation. Copy number variation (CNV) analysis detected malignant cells within scRNA-seq data, while intercellular interaction analysis examined communication between cell populations. Deconvolution of TCGA data revealed key immune populations, which were integrated into a prognostic model based on the adrenergic receptor signaling pathway and differentially expressed genes.
The adrenergic receptor signaling pathway was found in various immune cells, including T cells. scRNA-seq analysis revealed increased ADRB1 expression in T cells after neoadjuvant therapy. Immunofluorescence confirmed colocalization of ADRB1 with T cells, and fluorescence-activated cell sorting (FACS) showed that ADRB1 expression was elevated alongside exhaustion markers, while immune function markers were reduced. CNV analysis highlighted malignant cells in the tumor microenvironment, and intercellular interaction analysis explored ADRB1 T cells' role in immune support. Deconvolution of TCGA data identified ADRB1 T cells, SPP1 macrophages, and CD44 malignant cells, all of which were prognostically significant. A prognostic model constructed from the intersection of the adrenergic receptor signaling pathway and differentially expressed genes following neoadjuvant therapy showed a significant prognostic effect.
ADRB1 expression increases after neoadjuvant therapy in ESCC and correlates with poor prognosis. Our findings suggest ADRB1 as a potential prognostic biomarker and therapeutic target for post-neoadjuvant immunotherapy.
食管鳞状细胞癌（ESCC）因其侵袭性和晚期诊断预后不良而带来重大健康挑战。尽管存在这些挑战，但免疫检查点抑制剂等新兴疗法带来了希望。β1 - 肾上腺素能信号传导与T细胞耗竭有关，这会削弱ESCC中的免疫反应。阻断该途径可恢复T细胞功能。单细胞RNA测序（scRNA - seq）的最新进展使人们能够更深入地了解肿瘤异质性和免疫格局，为可能改善生存率并降低治疗抗性的个性化治疗策略打开了大门。
我们将scRNA - seq与批量RNA分析相结合，以探索ESCC中的肾上腺素能受体信号传导，重点关注新辅助治疗前后的变化。我们通过数据分析和实验验证鉴定出ADRB1 T细胞。拷贝数变异（CNV）分析在scRNA - seq数据中检测恶性细胞，而细胞间相互作用分析则检查细胞群体之间的通讯。对TCGA数据的反卷积揭示了关键免疫群体，这些群体被整合到基于肾上腺素能受体信号通路和差异表达基因的预后模型中。
在包括T细胞在内的各种免疫细胞中发现了肾上腺素能受体信号通路。scRNA - seq分析显示新辅助治疗后T细胞中ADRB1表达增加。免疫荧光证实ADRB1与T细胞共定位，荧光激活细胞分选（FACS）表明ADRB1表达与耗竭标志物一起升高，而免疫功能标志物降低。CNV分析突出了肿瘤微环境中的恶性细胞，细胞间相互作用分析探讨了ADRB1 T细胞在免疫支持中的作用。对TCGA数据的反卷积鉴定出ADRB1 T细胞、SPP1巨噬细胞和CD44恶性细胞，所有这些在预后方面都具有重要意义。由新辅助治疗后肾上腺素能受体信号通路和差异表达基因的交集构建的预后模型显示出显著的预后效果。
ESCC新辅助治疗后ADRB1表达增加且与预后不良相关。我们的研究结果表明ADRB1是新辅助免疫治疗后潜在的预后生物标志物和治疗靶点。
