ESTRO 2025 - Abstract Book

S3881

Radiobiology - Immuno-radiobiology

ESTRO 2025

3. Rajeev-Kumar, G. & Pitroda, S. P. Synergizing radiotherapy and immunotherapy: Current challenges and strategies for optimization. Neoplasia N. Y. N 36 , 100867 (2023). 4. Telarovic, I. et al. Delayed tumor-draining lymph node irradiation preserves the efficacy of combined radiotherapy and immune checkpoint blockade in models of metastatic disease. Nat. Commun. 15 , 5500 (2024).

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Digital Poster Harnessing particle radiation and cell cycle checkpoint inhibitors to induce immunogenic response in pancreatic cancer Ana Beatriz Dias 1,2,3 , Sylvia Kerschbaum-Gruber 1,2 , Ava Kleinwächter 3 , Joachim Widder 1 , Dietmar Georg 1 , Dea Slade 1,3,2 1 Radiation Oncology, Medical University of Vienna, Vienna, Austria. 2 NCR, MedAustron, Wiener Neustadt, Austria. 3 MaxPerutz Labs, Vienna BioCenter, Vienna, Austria Purpose/Objective: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common cancer types characterized by an alarmingly low survival rate. The asymptomatic profile of this cancer often results in late diagnosis with a locally advanced tumor, which precludes surgical resection. Currently, available treatment options such as chemotherapy and conventional radiotherapy are not efficient, which demands novel strategies to target pancreatic cancer. Particle therapy has emerged as a powerful tool in cancer treatment. Compared to photon radiotherapy, it allows for a higher and more localized dose delivery to the tumor site, thus sparing organs at risk. While the primary goal of radiotherapy is to induce cell death, it can also induce changes in the tumor microenvironment and activate immune signaling. The cGAS/STING and RIG-I/MAVS pathways are major components of our innate immune system and their activation through cytosolic nucleic acid sensing mediates the production of type I interferons. In cancer cells, P53 is often mutated, resulting in lower surveillance of their integrity across the cell cycle and a higher dependency on the G2/M checkpoint. Accordingly, cell cycle checkpoint inhibitors are being explored as tools to impair DNA damage response, thereby increasing cellular sensitivity to radiotherapy improving the chances of triggering an anti-tumor immune response. Material/Methods: PDAC cell lines (BxPC-3 and Panc-1) were used as models to test different combinatorial treatments. Protein and gene expression profiles, as well as an immunogenic cell death marker were assessed to study interferon response signaling and activation of the immune response. The treatment strategies included different cell cycle checkpoint inhibitors in combination with both photon-based radiotherapy (X-rays) and particle therapy (carbon ions). Moreover, these combinatorial treatments were also tested in CRISPR/Cas-9- generated STING- and MAVS- knockout cell lines. Results: Here we demonstrate that combinatorial treatments of cell cycle checkpoint inhibitors and radiotherapy can activate cGAS/STING and RIG-I/MAVS signaling, inducing a type I interferon response in pancreatic cancer cells. This induction is significantly decreased in BxPC-3 STING KO and Panc-1 MAVS KO cell lines. Inhibitors targeting ATR and CHK1 kinases show stronger synergistic effects when combined with carbon ion radiation in comparison with X rays. Moreover, the STING agonist diABZI can potentiate the immunogenic effects of carbon ions. Conclusion: Overall, our findings provide a rationale for combinatorial radiation-immunomodulatory treatment approaches in PDAC.

Keywords: PDAC, particle therapy, cell cycle checkpoints