The immunological consequences of radiation-induced DNA damage.
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Historically, our understanding of the cytotoxicity of radiation has centred on tumour cell-autonomous mechanisms of cell death. Here, tumour cell death occurs when a threshold number of radiation-induced non-reparable double-stranded DNA breaks is exceeded. However, in recent years, the importance of immune mechanisms of cell death has been increasingly recognised, as well as the impact of radiotherapy on non-malignant cellular components of the tumour microenvironment. Conserved anti-viral pathways that detect foreign nucleic acid in the cytosol and drive downstream interferon responses via the cGAS/STING pathway are key components of the immune response to radiation-induced DNA damage. In pre-clinical models, acute induction of a type 1 interferon response is important for both direct and abscopal tumour responses to radiation. Inhibitors of the DNA damage response show promise in augmenting this inflammatory interferon response. However, a substantial proportion of tumours show chronic interferon signalling prior to radiotherapy which paradoxically drives immunosuppression. This chronic interferon signalling leads to treatment resistance, and heterotypic interactions between stromal fibroblasts and tumour cells contribute to an aggressive tumour phenotype. The effect of radiotherapy on myeloid cell populations, particularly tumour-associated macrophages, has an additional impact on the immune tumour microenvironment. It is not yet clear how the above pre-clinical findings translate into a human context. Human tumours show greater intra-tumoural genomic heterogeneity and more variable levels of chromosomal instability than experimental murine models. High quality translational studies of immunological changes occurring during radiotherapy that incorporate intrinsic tumour biology will enable a better understanding of the immunological consequences of radiation-induced DNA damage in patients.
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radiation-induced DNA damage response
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J Pathol, 2019