Abstract：
The incidence of human papilloma virus-mediated oropharyngeal squamous cell carcinoma (OPSCC) has increased over the past 40 years, particularly among young individuals with a favorable prognosis; however, current therapy often leads to unfortunate side effects, such as dysphagia. Despite the emphasis on dysphagia in previous studies, there is an important research gap in understanding the correlation between neuronal changes and patient-reported and functional outcomes in patients with OPSCC. To address this issue, we examined pathologic tissue samples from patients with OPSCC using multiplex immunofluorescence staining and machine learning to correlate tumor-associated neuronal changes with prospectively collected patient-reported and functional outcomes. We found that tumor enrichment of adrenergic (TH+) and CGRP+ sensory-afferent nerves correlated with poorer swallowing outcomes. Functional electromyography recordings showed correlations between growing (GAP43+) and immature cholinergic (ChAT+DCX+) nerves and denervation patterns in survivors of OPSCC. A murine model of radiation-induced dysphagia further confirmed that immature cholinergic and CGRP+ nerves were correlated with impaired swallowing. Preclinical interventional studies also supported the independent contributions of CGRP+ and cholinergic (ChAT+) nerves to dysphagia in treated mouse models of OPSCC. Our results suggest that CGRP+ and ChAT+ neuronal signaling play distinct roles in tumor- and radiation-induced dysphagia in OPSCC and offer a comprehensive dataset on the neural landscape of OPSCC. These insights may guide early interventions for swallow preservation and the repurposing of neurology-related drugs, such as CGRP blockers, in clinical oncology and survivorship.
摘要：
人乳头瘤病毒介导的口咽鳞状细胞癌(OPSCC)的发病率在过去40年中有所上升,特别是在预后良好的年轻人中；然而，目前的治疗经常导致不幸的副作用，比如吞咽困难。尽管以前的研究强调吞咽困难，在理解OPSCC患者的神经元变化与患者报告和功能结局之间的相关性方面存在重要的研究差距.为了解决这个问题，我们使用多重免疫荧光染色和机器学习检查了OPSCC患者的病理组织样本,以将肿瘤相关的神经元变化与前瞻性收集的患者报告和功能结局相关联.我们发现肾上腺素能（TH）和CGRP感觉传入神经的肿瘤富集与吞咽结局较差相关。功能性肌电图记录显示OPSCC幸存者的生长（GAP43）和未成熟胆碱能（ChATDCX）神经与神经支配模式之间存在相关性。辐射诱导的吞咽困难的小鼠模型进一步证实未成熟的胆碱能神经和CGRP+神经与受损的吞咽相关。临床前干预研究也支持CGRP+和胆碱能(ChAT+)神经对OPSCC治疗小鼠模型中吞咽困难的独立贡献。我们的结果表明，CGRP和ChAT神经元信号在OPSCC的肿瘤和辐射诱导的吞咽困难中起着不同的作用，并提供了OPSCC神经景观的综合数据集。这些见解可能会指导早期干预以保存吞咽和重新利用神经病学相关药物。如CGRP阻断剂，临床肿瘤学和存活率。
