Main Session
Sep
28
PQA 03 - Digital Health Innovation and Informatics, Patient Safety & Quality, and Radiation and Cancer Biology
Presenter(s)
Hao Yu, MD, PhD - The First affiliated Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang
H. Yu1, K. Ding1, J. Ji2, J. Xie3, and S. Yan1; 1Department of Radiation Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China, 2Department of Neurosurgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China, 3Department of Ultrasound Medicine, the Second Affiliated Hospital of Zhe jiang Chinese Medical University, Hangzhou, China
Purpose/Objective(s):
Radiation-induced oral mucositis (RIOM) is a common dose-limiting toxicity with few mechanism-based interventions. We hypothesized that IL6 exerts stage-dependent effects in RIOM, worsening early epithelial injury but supporting late regeneration, thereby creating a therapeutic timing window for IL6 modulation.Materials/Methods:
A murine RIOM model was induced using localized head/neck RT (8 Gy*3), defining early, pre-ulcer, ulcer, and repair phases. WT and IL6-/- (KO) mice were assessed for body weight, epithelial thickness (H&E), apoptosis (cleaved caspase-3), proliferation (Ki67), and immune infiltration (CD45) with subset profiling (Ly6G, F4/80, B220). Epithelial signaling was evaluated by pSTAT3 (Y705) and IL6 localization. Primary human oral keratinocytes tested IL6 dependent pSTAT3 and proliferation with IL6R blockade. Timing was tested using anti-IL6 in WT mice (days 1-7 vs 8-15 post-RT) and exogenous IL6 supplementation in IL6-/- mice in the same windows. n=4-6 per time point; comparisons used t tests or ANOVA with multiplicity control; weight curves used repeated-measures models.Results:
Compared with WT, IL6-/- mice were more tolerant early after RT, with milder mucosal injury, but recovered more slowly during repair, showing impaired epithelial regeneration and delayed restoration of epithelial thickness. Consistent with this trajectory, early inflammatory cell entry into mucosa was attenuated in IL6-/- mice, with reduced CD45+ infiltration and decreased Ly6G+ and F4/80+ recruitment, whereas WT mucosa underwent more prominent ulcer-phase immune remodeling with an increased proportion of B220+ cells. Mechanistically, IL6 signal in RIOM localized predominantly to the epithelial compartment and tracked with pSTAT3 (Y705) activation; in oral keratinocytes, IL6R blockade reduced radiation-associated pSTAT3 and suppressed proliferation, supporting a role for IL6-STAT3 in repair-phase epithelial regeneration. Guided by these findings, we confirmed that timing determines therapeutic effect: short-course anti-IL6 on days 1-7 improved overall tolerance in WT mice, while initiating anti-IL6 on days 8-15 impaired recovery and weakened regenerative readouts. Exogenous IL6 supplementation in IL6-/- mice confirmed the timing effect, exacerbating disease when given early but improving recovery when given late.Conclusion:
IL6 functions as a stage-dependent regulator in RIOM, linking early inflammatory injury to late epithelial repair through IL6-STAT3 signaling. The data support time-restricted IL6 blockade in the pre-ulcer window rather than continuous suppression. This framework motivates translational testing of biomarker-guided scheduling and local cytokine modulation to reduce RIOM during head-and-neck RT while preserving mucosal healing.