Carbon ion or photon irradiation for PDAC immunomodulation

Pancreatic cancer remains among the deadliest cancer forms with rapid progression and poor survival. Due to the high rates of metastases at the time of clinical diagnosis, standard oncological therapies including surgery and radiotherapy yield little to no benefit. Therefore, new treatment strategies are urgently needed. For patients with highly metastatic cancers, such as pancreatic cancer, immunotherapy holds great promise. Training the patients individual immune system to detect and eradicate cancer lesions organism-wide may be the only true curative treatment for the majority of pancreatic cancer patients. However, the pronounced immunosuppressive tumor microenvironment of pancreatic cancer has so far hampered clinical success of immunotherapy. Beyond its primary tumor cell killing effects, radiation can remodel the tumor microenvironment and activate the anti-tumor immune response. Compared to conventional photon irradiation, carbon ion irradiation delivers more damage to the tumor while sparing the radiosensitive intestinal normal tissue and shows superior immunogenic effects. Indeed, our preliminary data supports the hypothesis of an immunomodulatory function of radiation in pancreatic cancer therapy. We showed that radiation with photons or carbon ions activates powerful anti-viral response programs in pancreatic cancer cells, culminating in the release of immune cell attractants. Immune cells are regulated, at least in part, by extracellular vesicles. Once thought of as cellular waste, they are now being increasingly recognized as intercellular messengers. We hypothesize that extracellular vesicles are crucial mediators of radiation-induced anti- tumor immunity in pancreatic cancer. We aim to investigate the activation of anti-viral response programs and their crosstalk with extracellular vesicles in pancreatic cancer cells, patient-derived tumor organoids and a mouse model using cutting-edge molecular biology techniques.