S2525
Radiobiology – Immuno-radiobiology
ESTRO 2026
Drake 1,2 , Colin Nixon 1 , Ed Roberts 1,2 , Seth Coffelt 1,2 , David Lewis 1,2 , Thomas G Bird 1,2 1 CRUK, Scotland Institute, Glasgow, United Kingdom. 2 School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. 3 CRUK RadNet Glasgow, University of Glasgow, Glasgow, United Kingdom Purpose/Objective: Optimal treatment for Hepatocellular Carcinoma (HCC) is curative, either resection, liver transplantation or local ablation, however, only ~20% of patients are eligible for this. Many patients present with incurable disease, for whom transarterial chemoembolisation or systemic chemotherapy are palliative options. Unfortunately, both have low responses and high rates of recurrence and progression. Stereotactic Ablative Radiotherapy (SABR) is a newly approved treatment option for a subset of HCC patients who are not eligible for resection or other local treatments. Retrospective studies report that this treatment modality has both clinical efficacy and feasibility, but prospective trials are required to better understand the role of SABR in HCC. SABR has the potential for good tumour control, but with recurrent and disseminated disease, there is a significant opportunity for integrating SABR into multimodal combination therapy. With this, there is a significant research opportunity in the preclinical space for models of SABR in HCC. Our aim is to develop a clinically relevant model to study targeted radiotherapy and systemic therapies in the treatment of HCC. Material/Methods: We have optimised an orthotopic transplant model injecting a mouse-derived HCC cell line into the immunocompetent murine liver, with contrast- enhanced CT guided SABR therapy using 20Gy single fraction in combination with immunotherapy. Treatment response and immune phenotyping was assessed using immunohistochemistry, flow cytometry and liver biochemistry. Results: We established a syngeneic orthotopic transplant model producing anatomically accurate, mono-focal liver tumours in immunocompetent mice. In keeping with clinical management and tratment planning we have implemented intravenous contrast-enhanced CT to enable reliable tumour detection and longitudinal CT imaging. SABR (20Gy) induced significant DNA damage in tumours, with minimal off-target effects on surrounding liver and organs. Irradiated tumours showed reduced proliferation (BrdU) and increased senescence (p21). CD8+ T cell infiltration was observed in te tumours 7 days post-radiotherapy. 2-week combination therapy with SABR and anti-PD1 altered the tumour-infiltrating T regulatory cell (FoxP3+) population. Furthermore, combining SABR with VEGFR
inhibition and anti-PDL1 (modelling atezolizumab- bevacizumab) significantly reduced tumour volume compared to controls. Conclusion: Our orthotopic transplant model provides a robust platform to study SABR in HCC. It enables clinically relevant imaging, precise radiotherapy delivery, and immune profiling in an immunocompetent setting. This model supports the evaluation of SABR in combination with systemic therapies, including immunotherapy, and may help identify strategies to
enhance clinical responses in HCC patients. Keywords: pre-clincal, HCC, stereotactic
Proffered Paper 1982
Mean dose rate-dependent skin sparing by FLASH- RT through suppressing the lysosomal membrane permeabilization-NLRP3 inflammasome axis in macrophages Chen Wang 1 , Ziqi Zhou 1 , Xin Liu 1 , Fuquan Zhang 1 , Jing Zhao 2 , Ke Hu 1 1 Department of Radiation Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. 2 Department of Radiation Oncology, Beijing Shijitan Hospital ， Capital Medical University, Beijing, China Purpose/Objective: FLASH radiotherapy has shown promise in normal tissue protection, yet its key physical parameters and biological mechanisms remain unclear, hindering clinical translation. This study aims to evaluate the influence of mean dose rate(MDR) on the skin-sparing effect of FLASH-RT and to investigate the role of the "lysosomal membrane permeabilization–NLRP3 inflammasome activation" axis. Material/Methods: Eight-week-old male Balb/c mice were subjected to electron beam-based FLASH-RT at a range of MDRs of 90, 210, 450, and 750 Gy/s, with conventional irradiation serving as the control. Gross and pathological skin responses were continuously monitored within 3 months to evaluate the impact of MDR on the skin. To investigate the radiation effects, BMDMs were exposed to the same MDR spectrum. Subsequently, we assessed alterations in cell viability, polarization status, and key signaling molecules of the lysosomal membrane permeabilization and NLRP3 inflammasome activation pathways. Macrophage depletion and pharmacological interventions targeting intracellular ROS, NLRP3, and lysosomal membrane stability were performed respectively to evaluate their impact on the FLASH effect in mouse skin and macrophages.
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