Abstract 4573: Localized synchrotron radiation in mice induces persistent systemic genotoxic events mediated by the functional immune system

Abstract The discovery of the radiation-induced bystander effect has expanded knowledge of radiobiological mechanisms of ionizing radiation. A counterpart in vivo phenomenon is the radiation-induced abscopal effect (RIAE). It is not known how radiation settings affect non-targeted normal tissues and therefore the risk of adverse RIAE. At the Australian Synchrotron we examined systemic effects of microbeam radiotherapy (MRT) and broad beam (BB) configurations, in mice that were locally exposed to a very short pulse of a high dose-rate synchrotron beam (49 Gy/sec). We determined how radiation volume and dose impact the RIAE. C57BL/6 mice were irradiated with 10 or 40 Gy incident dose of MRT or BB in an 8x8, 8x1, or 2x2-mm area of the right hind leg. Blood samples, irradiated skin and a variety of normal unirradiated tissues were collected for DNA damage analysis of double-strand breaks (DSBs) quantified as gamma-H2AX foci and oxidatitive clustered DNA lesions (OCDL). OCDLs elevated in a wide variety of unirradiated normal tissues. In out-of-field duodenum, a trend for elevated apoptotic cells was observed, however DSBs elevated only after exposure to lower doses. These genotoxic events were accompanied by changes in concentrations of MDC, CCL2/MCP1, Eotaxin, IL-10, TIMP-1, VEGF, TGFβ-1 and TGFβ-2 plasma cytokines and by changes in frequencies of macrophages, neutrophils and T-lymphocytes in duodenum. Overall, systemic radiation responses were dose-independent (1). The MRT irradiations was repeated in immune-deficient mice: NSG, CCL2 knock-outs, and in C57BL/6 mice treated with anti-CSF1R antibody which effectively depletes macrophages. Strikingly, these effects and the abscopal innate and adaptive immune effector responses were completely or partially abrogated in the mice with various immune deficiencies, highlighting the role of the functional immune system in propagation of systemic genotoxic effects of radiation. These findings have implications for the planning of therapeutic and diagnostic radiation to reduce the risk of radiation-related adverse systemic effects. 1. Ventura et al, Cancer Research, e-pub (2017). Citation Format: Jessica Ventura, Pavel Lobachevsky, Jason Palazzolo, Helen Forrester, Nicole Haynes, Alesia Ivashkevich, Andrew Stevenson, Christopher Hall, Vassilis Gorgoulis, John Hamilton, Alexandros Georgakilas, Calr Sprung, Olga A. Martin. Localized synchrotron radiation in mice induces persistent systemic genotoxic events mediated by the functional immune system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4573.