A Functional Immune System Is Required For The Systemic Genotoxic Effects Of Localised Irradiation.

INTRODUCTION: Non-targeted effects of ionizing radiation, by which unirradiated cells and tissues are also damaged, are a relatively new paradigm in radiobiology. We recently reported radiation-induced abscopal effects (RIAEs) in normal tissues, namely DNA damage, apoptosis, and activation of the local and systemic immune responses in C57BL6/J mice after irradiation of a small region of the body [1]. High dose-rate synchrotron-generated broad beam or multi-planar X-ray microbeam radiation therapy (MRT) was used with various field sizes and doses. The present study explores components of the immune system involved in the generation of these abscopal effects.

METHODS AND MATERIALS: Mice with various immune deficiencies were irradiated with the MRT beam: (i) SCID/IL2γR-/- (NOD SCID gamma, NSG) mice, (ii) wild type C57BL6/J mice treated with an antibody blocking macrophage colony-stimulating factor 1 receptor (CSF-1R) which depletes and alters the function of macrophages, and (iii) chemokine ligand 2/monocyte chemotactic protein 1 (CCL2/MCP1) null mice. Complex DNA damage, i.e. DNA double-strand breaks (DSBs), oxidatively-induced clustered DNA lesions (OCDLs) and apoptotic cells in tissues distant from the irradiation site, were measured as RIAE end-points, and compared with those in wild type C57BL6/J mice.

RESULTS: Wild-type mice accumulated DSBs, OCDLs and apoptosis, enforcing our RIAE model. However, these effects were completely or partially abrogated in mice with immune disruption, highlighting the pivotal role of the immune system in propagation of systemic genotoxic effects after localised irradiation.

CONCLUSION: These results underline the importance of delineating not only the best strategies for tumour control, but also importance of mitigating systemic radiation toxicity.