Ahmed Atta 1, Farnoush Farahpour 1
1 University of Duisberg - Essen (Essen, Germany)
Objectives
Radiation therapy (RT) is a standard treatment for thoracic cancers such as lung cancer and lymphoma. However, exposure of healthy lung tissue can lead to radiation-induced lung injury (RILI), which presents as acute pneumonitis and may progress to pulmonary fibrosis. The biological mechanisms linking epithelial damage to immune activation are complex and not fully understood. To investigate these processes, we developed a mechanistic Quantitative Systems Pharmacology (QSP) model to describe RILI progression and identify potential drivers of toxicity.
Methods
We expanded a previously published QSP model by refining the representation of immune–epithelial interactions and incorporating a linear–quadratic radiation module to estimate alveolar epithelial cell death as a function of dose and repair capacity. The final model includes 40 state variables and more than 170 parameters. Given the model complexity, we performed global sensitivity analysis using Sobol indices to determine the most influential parameters and to support model calibration. The framework integrates preclinical data from irradiated mice, including flow cytometry and single-cell RNA sequencing datasets across multiple radiation doses.
Results
The model reproduces the temporal interplay between innate and adaptive immune responses after radiation exposure. Early activation of neutrophils, M1 macrophages, and plasmacytoid dendritic cells drives the acute inflammatory phase within the first 24–48 hours. In contrast, adaptive immune responses involving Th1, Th17, and cytotoxic T lymphocytes show delayed activation patterns.
Sensitivity analysis identified several key drivers of RILI progression. The death rate of damaged alveolar epithelial cells had a sustained influence on innate immune activation over time. Neutrophil activation was particularly important during early time points (Days 4–10) but declined in later stages. Within the adaptive compartment, dendritic cell activation was relevant in the early phase, whereas Th17 activation gained importance over time, suggesting a role in the development of chronic inflammation and fibrosis.
Conclusions
This mechanistic QSP framework provides a structured approach to studying radiation-induced lung injury and highlights key immune processes associated with toxicity. Although the model is still under refinement, preliminary results demonstrate its potential to prioritize relevant biological mechanisms and to support future biomarker-driven strategies in radiation therapy.
References:
1.Yan, Yujie, et al. “Exploration of radiation-induced lung injury, from mechanism to treatment: a narrative review.” Translational lung cancer research 11.2 (2022): 307.
2.Dai, Wei, et al. “A prototype QSP model of the immune response to SARS‐CoV‐2 for community development.” CPT: pharmacometrics & systems pharmacology 10.1 (2021): 18-29.
3.Chaput, Genevieve, and Laura Regnier. “Radiotherapy: Clinical pearls for primary care.” Canadian Family Physician 67.10 (2021): 753.
Reference: PAGE 34 (2026) Abstr 12107 [www.page-meeting.org/?abstract=12107]
Poster: Drug/Disease Modelling - Oncology