Abstract PO-049: The neural landscape is associated with functional outcomes for patients with oropharyngeal squamous cell carcinoma
Authors: Islam Shajedul , Gleber-Netto Frederico O. , Mulcahy Collin F. , Glaun Mica D. E. , Hunt Patrick J. , Williams Michelle D. , Barbon Carly E. , Zhao Weilu , Adebayo Adewale , Akhter Shamima , Xie Tongxin , Yaman Ismail , Burks Jared K. , Gomez Javier , Woodman Karin , Lever Teresa E. , Hutcheson Katherine A. , Amit Moran 
Published: September 2023

Abstract
Despite the excellent prognosis of patients with oropharyngeal squamous cell carcinoma (OPSCC), long-term functional impairment (e.g., dysphagia) is a major burden for many patients. Recent studies have explored the role of pharyngeal constrictors and muscle fibrosis in dysphagia. However, to date, no study has examined the association between the OPSCC neural microenvironment and posttreatment functional impairment. We hypothesized that cancer-related neuronal changes in the OPSCC tumor microenvironment (TME) would affect patients’ prognoses. Therefore, in the present study, we investigated whether cancer-related changes in the tumor neuronal microenvironment influence functional outcomes in patients with OPSCC. Prospectively collected, patient-reported outcomes (i.e., from the MD Anderson Symptom Inventory [MDASI] and the MD Anderson Dysphagia Inventory [MDADI]) and functional outcomes from the Dynamic Imaging Grade of Swallowing Toxicity [DIGEST] for patients with OPSCC were collected (n=29). OPSCC tissue samples were obtained from surgically treated patients, and multiplex/high-plex immunofluorescence and machine learning techniques were used to correlate neuronal changes with prospectively collected patient data. Electromyography was performed to assess the neuronal populations involved in neuropathies after treatment. A murine animal model of dysphagia was also used to correlate the neuronal changes. The results showed that sensory nerves with adrenergic features (CGRP+TH+) were associated with perineural and lymphovascular invasion. In addition, we found that human papillomavirus associated OPSCC was associated with an enrichment of parasympathetic progenitors (VIP+DCX+). Poor MDASI scores were associated with CGRP+, adrenergic (TH+), or CGRP+TH+ innervation, and growing progenitor neurons (GAP43+DCX+) were associated with improved oral symptoms. Swallowing, measured by MDADI scale revealed that patients with tumors enriched with growing (GAP43+), parasympathetic (VIP+), and neuronal progenitor (DCX+) neurons reported poor swallowing perception; subgroup electromyography analysis confirmed our findings. Quantitative swallowing assessment with DIGEST by speech language pathologists revealed that TMEs innervated by CGRP+, TH+, and MBP+ neurons were associated with poor swallowing functions. Finally, using a murine model of dysphagia we confirmed that sensory (CGRP+), myelinated (MBP+), and cholinergic parasympathetic (CHAT+) or progenitor (CHAT+DCX+) enrichment was associated with denervation and downstream dysphagia. In conclusion, our results show that neuronal changes are correlated with clinical features in OPSCC patients. Patients’ functional outcomes after therapy completion are influenced by distinct nerve populations in the TME. These benchmark data should be further evaluated as a potential target for cancer survivors with dysphagia and as a biomarker for patients who might need escalated swallowing rehabilitation during and after treatment for OPSCC.
Citation Format: Shajedul Islam, Frederico O. Gleber-Netto, Collin F. Mulcahy, Mica D. E. Glaun, Patrick J. Hunt, Michelle D. Williams, Carly E. Barbon, Weilu Zhao, Adewale Adebayo, Shamima Akhter, Tongxin Xie, Ismail Yaman, Jared K. Burks, Javier Gomez, Karin Woodman, Teresa E. Lever, Katherine A. Hutcheson, Moran Amit. The neural landscape is associated with functional outcomes for patients with oropharyngeal squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-049.