Carbon ion or photon irradiation for PDAC immunomodulation

• Applicants: Dr. Rene-Filip Jackstadt; Dr. Styliani Logotheti, Ph.D.; Dr. Francesca Pagliari
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 561811975

Pancreatic cancer progresses rapidly and has poor survival rates. Pancreatic ductal adenocarcinoma (PDAC) is refractory to current standard-of-care treatment options due to the immunosuppressive tumor microenvironment (TME). Radiation shows local and systemic immunomodulatory properties and may remodel the TME, thus enhancing the therapeutic efficacy. Radiation modalities with higher tissue-sparing potential, in particular carbon ions (C-ions), are emerging as regulators of the tumor-immune ecosystem. However, the relevant intra-tumoral and intercellular mechanisms are poorly understood, especially considering that different radiation types activate distinct pathway trajectories, resulting in different tumor-host interactions. Our preliminary work shows that X-rays promote anti-tumor immune effects in PDAC by activating the STING and MAVS signaling axis and type I interferon (IFN-I) response. Mechanistically, the effects of immune cells are mediated, at least in part, by extracellular vesicles (EVs). Endogenous retroviruses (ERVs), viral RNA sensors (such as RIG-I), and anti-viral defense pathways are co-activated in irradiated cells. Thus we hypothesize that intra-tumoral build-up of ERV-associated nucleic acids after irradiation triggers viral mimicry, which, in turn, shapes and potentiates the anti-tumor immune response. In this project we aim to investigate (a) the activation of STING and MAVS signaling by C-ions versus X-rays in PDAC, (b) the crosstalk between ERV-induced viral mimicry and STING/MAVS signaling and its effects on IFN-I response and EV production, (c) the qualitative and quantitative changes of irradiation-released EVs and their downstream effects on TME. We will use established pipelines for isolating and characterizing irradiation-induced EVs, in combination with CRISPR/Cas9-based PDAC models, functional assays in vitro, multi-omics (integrative scRNAseq, Dia Mass Spectrometry, and highly multiplexed imaging), tumor organoids, and orthotopic mouse models. The comparative characterization of the of X-rays- versus C-ions-driven immunomodulatory effects holds translation potential for improving the stratification of patients likely to respond to each radiotherapy type based on their molecular tumor profiles.

• DFG Programme: Research Grants
• International Connection: Austria
• Partner Organisation: Fonds zur Förderung der wissenschaftlichen Forschung (FWF)
• Cooperation Partners: Professor Dr. Dietmar Georg, Ph.D.; Sylvia Kerschbaum-Gruber, Ph.D.; Professorin Dr. Dea Slade, Ph.D.; Dr.-Ing. Markus Zeilinger
• Co-Investigator: Professor Joao Seco, Ph.D.