57: Positron emission tomography (PET) isotope production from laser-driven proton

Abstract

The role of autophagy in radiation response of tumors remains largely elusive. By using a dual pharmacological and genetic inhibitory approach, we identified a dual role of autophagy in the response of cancer cells to ionizing radiation. First, we observed that the depletion of essential autophagy-relevant gene products, such as ATG5 and Beclin 1, increased the sensitivity of human or mouse cancer cell lines to irradiation, both in vitro (where autophagy inhibition increased radiation-induced cell death and decreased clonogenic survival) and in vivo, after transplantation of the cell lines into immunodeficient mice (where autophagyinhibition potentiated the tumour growthinhibitory effect of radiotherapy). Secondly, when tumour proficient or deficient for autophagy were implanted in immunocompetent mice, defective autophagy reduced the efficacy of radiotherapy. Indeed, radiotherapy elicited an anti-cancer immune response that was dependent on autophagy-induced ATP release from stressed or dying tumour cells and was characterized by dense lymphocyte infiltration of the tumour bed. Intratumoural injection of an ecto-ATPase inhibitor restored the immune infiltration of autophagy-deficient tumours post radiotherapy and improved the growth-inhibitory effect of ionizing irradiation. Our results reveal that beyond its cytoprotective function, autophagy confers immunogenic properties to tumours, hence amplifying the efficacy of radiotherapy in an immunocompetent context. This has far-reaching implications for the development of pharmacological radiosensitizers.