ESTRO 2025 - Abstract Book

S3877

Radiobiology - Immuno-radiobiology

ESTRO 2025

4. Linge A, et al. Low Cancer Stem Cell Marker Expression and Low Hypoxia Identify Good Prognosis Subgroups in HPV(-) HNSCC after Postoperative Radiochemotherapy: A Multicenter Study of the DKTK-ROG. Clin Cancer Res. 2016;22: 2639-2649.

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Digital Poster Cytosolic nucleic acid sensors and interferon beta-1 activation drive radiation-induced anti-tumour immune effects in human pancreatic cancer cells Sylvia Kerschbaum-Gruber 1,2 , Ava Kleinwächter 1 , Katerina Popova 1 , Alexandra Kneringere 1 , Lisa-Marie Appel 1 , Katharina Stasny 1 , Anna Röhrer 1 , Ana Beatriz Dias 1 , Johannes Benedum 1 , Lena Walch 3 , Andreas Postl 1 , Sandra Barna 1 , Bernhard Kratzer 4 , Winfried Pickl 4 , Altuna Akalin 5 , Filip Horvat 3 , Vedran Franke 5 , Joachim Widder 1 , Dietmar Georg 1 , Dea Slade 1,3,2 1 Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria. 2 Non-clinical Reserch, MedAustron, Wr. Neustadt, Austria. 3 Max Perutz Labs, Vienna Biocenter Campus, Vienna, Austria. 4 Institute of Immunology, Medical University of Vienna, Vienna, Austria. 5 Max Delbrück Center, The Berlin Institute for Medical Systems Biology, Berlin, Germany Purpose/Objective: Pancreatic ductal adenocarcinoma (PDAC) patients have a low overall survival due to late diagnosis, early metastatic spread and high rates of radio- and chemotherapy resistance. Moreover, standard photon-based radiotherapy is limited by tumor-adjacent sensitive organs at risk. Immunotherapy has demonstrated remarkable successes in a subset of tumors but so far has failed in PDAC. Particle radiotherapy is an emerging cancer treatment option, characterized by increased relative biological effectiveness (RBE) and improved treatment conformity compared to photon radiotherapy. Photon-based radiation has demonstrated the ability to induce in situ vaccine sites, synergizing with immune checkpoint blockade (ICB) and converting previously unresponsive into responsive tumors. Immunogenicity of particles as compared to conventional radiotherapy is highly relevant in the context of perspective combinatorial treatments. Combining the advantages of particle radiation with ICB may offer new hope for PDAC patients. The in situ vaccine effects of radiation are based on accumulation of cytosolic nucleic acids, which trigger a type 1 interferon (IFN-I) response. Material/Methods: Multiple clinically relevant doses of X-rays and protons are compared to assess immunogenic cell death, cytosolic nucleic acid accumulation and induction of immunomodulatory effects of radiation. Immunofluorescence analysis, CRISPR/Cas9-mediated STING- and MAVS knockouts, ELISA, flow cytometry and pharmacological targeting of STING or NF-κB reveal radiation-induced immunogenicity in three human PDAC cell lines. Furthermore, the RBE of protons are derived from cell survival curves using the linear quadratic fit model. Results: We demonstrate cytosolic dsDNA accumulation after X-rays or protons in PANC-1, MIA PaCa-2 and BxPC-3. Both cytosolic DNA and RNA sensing induce IFN-I accompanied by an NF-κB-mediated pro-inflammatory cytokine response. Time course analysis reveals a delayed immunogenic response several days after the last irradiation fraction. A hypofractionation regimen of 3x8 Gy is more immunogenic compared to irradiations of 2 Gy, 8 Gy or 24 Gy single doses. Protons yield similar immunogenic effects compared to equal physical doses of X-rays. Both radiation modalities not only stimulate immunogenic responses but also upregulate Galectin-1, a T-cell suppressive cytokine. Conclusion: All three cell lines yield RBE 10 of approximately 1.1, supporting the continued use of a static RBE of 1.1 for protons in clinical PDAC treatment planning. X-ray- or proton irradiation induces a range of immunogenic alterations in human